Electrochemical C(sp 3)-H Fluorination

Article abstract of DOI:10.1055/s-0037-1611737

A simple and robust method for electrochemical alkyl C-H fluorination is presented. Using a simple nitrate additive, a widely available fluorine source (Selectfluor), and carbon-based electrodes, a wide variety of activated and unactivated C-H bonds are converted into their C-F congeners. The scalability of the reaction is also demonstrated with a 100 gram preparation of fluorovaline.

Full text of DOI:10.1055/s-0037-1611737

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
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Electrochemical C(sp3)–H Fluorination
Yusuke Takahiraa
Miao Chena
Yu Kawamataa
Pavel Mykhailiuka,b
Hugh Nakamuraa
Byron K. Petersa
Solomon H. Reisberga
Chao Lia
• >20 examples
• unactivated
2° & 3° C(sp3)–H
• mild conditions
• scalable
• comparison with lit. methods
Selectfluor
NaNO3
R1
R2
H
R1
R2
R1
R2
F
R1
F
R2
or
or
R3
H
R3
H
H
Electrochemical
C(sp3)–H fluorination
Longrui Chenc
Tamaki Hoshikawad
Tomoyuki Shibuguchid
Phil S. Baran*a
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a Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, United States
pbaran@scripps.edu
b Enamine Ltd., Chervonotkatska 78, 02094 Kyiv, Ukraine and Taras Shevchenko National University of Kyiv, Chemistry
Department, Volodymyrska 64, 01601 Kyiv, Ukraine
c Asymchem Life Science (Tianjin), Tianjin Economic-Technological Development Zone, Tianjin 300457, P. R of China
d Discovery, Medicine Creation, Neurology Business Group, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, 300-2635, Japan
Published as part of the Cluster Electrochemical Synthesis and Catalysis
Received: 23.01.2019
Accepted after revision: 27.01.2019
Published online: 01.03.2019
able approach to C(sp3)–H fluorination that utilizes Select-
fluor in a unique way when coupled to anodic oxidation in
the presence of a nitrate additive.
DOI: 10.1055/s-0037-1611737; Art ID: st-2018-b1827-c
A truncated optimization table is depicted in Scheme
1B, wherein Selectfluor was chosen as a fluorine atom do-
nor based on its wide availability. From a reactivity stand-
point, one could also envisage three distinct roles for Select-
fluor: as (1) its own electrolyte due to its ionic nature; (2)
an electrophilic fluorine source; and (3) itself a mediator
similar to quinuclidine.3 Using 1 as a model substrate, the
impact of various reaction parameters was investigated
(Scheme 1B). The fully optimized conditions called for the
use of Selectfluor (3.0 equiv) and sodium nitrate (0.2 equiv)
in acetonitrile with a pair of reticulated vitreous carbon
(RVC) electrodes at 3 mA to deliver the desired fluorinated
product 2 in 62% NMR yield (54% isolated, entry 1). Not sur-
prisingly, the reaction was found to be sensitive to oxygen,
as is rationalized from the proposed radical chain mecha-
nism (vide infra, entry 2). The reaction was confirmed to be
electrochemically driven and required a constant supply of
current (entry 3). Extensive screening revealed that the so-
dium nitrate was essential for the initiation as well as for
improving the reproducibility of this reaction (entries 4 and
5). The peculiar use of nitrate has precedent in the electro-
chemical literature; nitrate is known to be oxidized anodi-
cally to generate reactive radical species capable of ab-
stracting hydrogen from substrates.6 The alternative fluori-
nating agent Selectfluor II (B) was also evaluated and did
not improve the yield (entry 6). The likely role of Selectfluor
as a mediator was supported by the fact that other electro-
Abstract A simple and robust method for electrochemical alkyl C–H
fluorination is presented. Using a simple nitrate additive, a widely avail-
able fluorine source (Selectfluor), and carbon-based electrodes, a wide
variety of activated and unactivated C–H bonds are converted into their
C–F congeners. The scalability of the reaction is also demonstrated with
a 100 gram preparation of fluorovaline.
Key words organic synthesis, electrochemistry, fluorination, C–H
functionalization, radicals
Within the realm of synthetic organic electrochemis-
try,1 few applicable options exist for the C–H functionaliza-
tion of unactivated aliphatic centers. In 2016 our lab reported
a simple and inexpensive method for the oxidation of allylic
C–H bonds featuring N-hydroxytetrachlorophthalimide as a
mediator for hydrogen atom transfer.2 Shortly thereafter, it
was found that the use of quinuclidine as mediator allowed
for the oxidation of stronger C–H bonds such as unactivated
methylenes.3 Based on requests from industrial collabora-
tors in medicinal chemistry, we were compelled to extend
this precedent to the problem of C–H fluorination. Al-
though both photochemical4 and purely chemical means5
exist for accomplishing such a transformation (Scheme 1A),
an electrochemical alternative was pursued to determine if
there was any specific advantage in terms of scalability
and/or selectivity. Disclosed herein is a practical and scal-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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Y. Takahira et al.
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(Scheme 2A), simple acyclic and cyclic alkanes were fluori-
nated, including those bearing esters (3 and 4), ketones (5
and 6), and even alkyl bromides (8). In the case of sclareo-
lide, the reaction gave a mixture of the corresponding fluo-
rinated compounds 9 in 58% yield. Notably, even in the ab-
sence of sodium nitrate, 9 was obtained in 67% yield. Fluori-
nation of tertiary systems generally proceeded in higher
yield (Scheme 2B). Thus, acyclic, amino acid derivatives,
and adamantanes were all fluorinated in synthetically use-
ful yields. Fluorination of unsubstituted adamantanes gen-
erally led to a mixture of di-/tri-fluorinated products in rea-
sonable yields, whereas high yields of mono-fluorination
were observed when only one tertiary C–H bond was avail-
able (19 and 20). Access to fluorinated amino acids (12, 13,
17, and 18) is a promising application with known uses in
drug discovery contexts.9 This methodology was also field-
tested at Eisai where numerous building blocks were sub-
jected to electrochemical fluorination and synthetically
useful yields of valuable fluorinated products emerged (24,
25, and 26 in Scheme 2D). In order to demonstrate the sim-
plicity with which this chemistry could be conducted on
scale, a 100-gram scale fluorination of protected L-valine 27
provided the corresponding fluorinated adduct 12 in 78%
yield (Scheme 2E) without significant erosion of enantiopu-
rity (96% ee, see the Supporting Information). This was ac-
complished using a simple batch reactor (see the Support-
ing Information for details), but in principle could also be
easily adopted to a flow setup.
A. Inspiration for electrochemical C(sp3)–H fluorination
(Refs. 4–5)
C(sp3)–H
C(sp3)–F
[expensive]
[difficult to scale]
R1
R2
H
R1
R2
F
This Work
Electrochemical C(sp3)–H fluorination
R3
R3
[unactivated]
[100 g scale]
[mild] [practical] [scalable] [sustainable]
B. Optimization of electrochemical C(sp3)–H fluorinationa
A
H
F
Me
Me
Me
Me
O
O
(+)RVC
(–)RVC
Selectfluor (A) (3.0 equiv)
NaNO3 (0.2 equiv), MeCN
alternate polarity (2 min)
3.0 mA, 2.0 F/mol
O
O
F
F
1
2
Entry
Deviation from above
Yield (%)b
1
2
none
62 (54)c
open to air
nd
3
no electricity
no NaNO3
nd
4
nd
5
1.0 equiv of NaNO3
B instead of A
C instead of A
D instead of A
(+)RVC/(–)Ni foam
6 mA instead of 3 mA
42
6
60
7
nd
8
ndd
13e
42
9
10
a 0.1 mmol. See Supporting Information for full details. b 19F NMR yield.
nd = not detected. c Isolated yield. d 1.0 equiv of n-Bu4NBF4 was added
as electrolyte. e No alternate polarity.
SO2Ph
R
F
N
N
BF4
R = Cl (A)
R = H (B)
SO2Ph
N
N
F
2BF4
(C)
(D)
F
Scheme 1 (A) Electrochemical C(sp3)–H fluorination. (B) Reaction de-
velopment
Regarding the limitations of this method, several sub-
strates delivered mixtures of isomers, showed no reaction,
or decomposed under standard conditions (Scheme 2C). For
example, C–H bonds adjacent to a heteroatom are prone to
oxidation, resulting in degradation. No product formation
but partial decomposition was observed in the case of
strained systems such as the bicyclo[2.1.0]pentane frame-
work 22 after passing a total charge of 1.0 F/mol at 1.5 mA
under constant current conditions. Certain nucleophilic
groups were not tolerated under the current conditions. Re-
gardless of these limitations, the operational simplicity, re-
producibility, and short reaction times are useful attributes
of the present method. To further simplify the reaction con-
ditions, it is worth noting that in the cases of sclareolide,
adamantane, and the protected valine sodium nitrate was
not required for efficient initiation of the reaction.
A proposed mechanism for electrochemical C–H fluori-
nation is described in Scheme 3. Considering the fact that
this reaction is a net redox-neutral transformation and that
the regioselectivity is analogous to that of other radical-
based C–H functionalizations, a radical chain mechanism is
proposed. Initially, a small amount of carbon radical is gen-
erated by either direct or nitrate-mediated electrochemical
oxidation of a substrate. Subsequent fluorination by Select-
fluor delivers radical cation 28, which can then abstract hy-
drogen from the substrate. Oxidative initiation was con-
firmed by conducting a reaction in a divided cell (without
philic fluorinating sources (some known to capture nucleo-
philic radicals) failed to effect this transformation (entries 7
and 8).
The use of a Ni foam cathode instead of RVC had a dele-
terious effect upon this reaction (entry 9, for a detailed
summary of electrodes screened, see the Supporting Infor-
mation). Finally, increasing the current to 6 mA also result-
ed in lower yield (entry 10). In this case, the reaction result-
ed in incomplete conversion of the starting material with
unidentified byproducts, likely due to the higher voltage.
With an optimized set of conditions in hand, the utility
of electrochemical C–H fluorination was explored. The gen-
erality of this transformation is shown in Scheme 2,7
demonstrating efficient C–H fluorination on various classes
of molecules including terpenes, amino acids and pharma-
ceutically relevant structures. Comparisons with chemical
conditions available in the literature are also included in the
Scheme 2. In general, fluorination occurs at the unactivated
secondary or tertiary C–H bonds that are the most distal
from the electron-withdrawing group. This regioselectivity
tracks with innate reactivity towards an electrophilic oxi-
dant8 and is reminiscent of the selectivity of electrochemi-
cal unactivated C–H oxidation,3 which strongly suggests
that the C–H abstraction step proceeds via a mediated radi-
cal mechanism. Within the realm of secondary systems
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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Y. Takahira et al.
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Scheme 2 Electrochemical fluorination: Scope and applications
nitrate), where reaction progress was observed only in the
anodic chamber. Evidence for a radical chain reaction in-
cludes the observation of >100% current efficiency in the
reaction shown in Scheme 4. The necessity of constant elec-
tricity supply for this radical chain process is not unusual
because 28 can undergo nonproductive reaction pathways
such as fragmentation and hydrogen abstraction from sol-
vent or decomposed material.
strates do not require a nitrate additive (vide supra), which
clearly indicates that nitrate radical is not crucial for the re-
action progress. In contrast, DABCO-containing fluorine
sources are essential for successful reactions (see Scheme 1).
Regarding the capability of nitrate as initiator, it is known
that nitrate can be electrochemically oxidized.10 Cyclic vol-
tammetry indicated that oxidation of nitrate indeed oc-
curred at +2.2 V in acetonitrile with respect to Ag/AgCl ref-
erence electrode (see the Supporting Information).
We assume that the role of nitrate is to improve the effi-
ciency of initiation, rather than as a chain carrier. This is
supported by the fact that C–H fluorination of several sub-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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Y. Takahira et al.
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R1
R2
compound
photochema
electrochemb
NO3
A
H
H
Mediated
oxidation
Direct oxidation
24
25
29
68% (H:F = ca. 10:7)
78% (H:F = ca. 2:1)
– e
26%c
19%c
43%
57%
R1
R2
NO3
+ H
H
Cl
Cl
2BF4
N
N
a Selectfluor (2.2 equiv), 1,2,4,5-tetracyanobenzene (0.1 equiv), MeCN, 26 W
UV-B CFL, 13–15 h. b Selectfluor (3.0 equiv), NaNO3 (0.2 equiv), MeCN,
(+)RVC/(–)RVC, 3.0 mA, alternate polarity (2 min). c 1H NMR yield.
N
N
H
F
2BF4
Selectfluor
• Mediator
• [F] donor
• Electrolyte
Propagation
O
F
R1
H
R2
Boc
N
O
F
OMe
H
N
F
H
Cl
N
F/H
R1
R2
Cl
N
N
2BF4
F
H
24
25
29
Cl
28
O
Scheme 3 Proposed mechanism
Figure 1 Comparison of electrochemical and photochemical C–H fluo-
rination using actual med-chem intermediates
O
O
Me
Me
1
1
O
O
2
2
Selectfluor (3.0 equiv)
H
Me
H
Me
F
Funding Information
3
3
(+)RVC/(–)Ni foam
MeCN
3.0 mA, 0.25 F/mol
H
H
Me Me
Me Me
Financial support for this work was provided by the NSF (#1740656),
Pfizer, AGC Inc. (to Y.T.), Nankai University (to M.C.), the George E.
Hewitt Foundation (to Y.K.), a Fulbright Scholar Fellowship (to P.M.),
JSPS (to H.N.), the Swedish Research Council (VR 2017-00362 to
B.K.P.), NSF GRFP (#2017237151) and a Donald and Delia Baxter Fel-
9
52% by 19F NMR
(2α:3α:2β = ca. 75:20:5)
Scheme 4 Evidence for a radical chain mechanism: 0.25 equiv of elec-
trons delivers >50% yield
lowship (to S.H.R.).
N
ati
o
n
a
lS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
(1
7
4
0
6
5
6)Nati
o
n
a
lS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
(2
0
1
7
2
3
7
1
5
1)
Thus, nitrate oxidation likely occurs before any direct
anodic C–H abstraction.11 Taken together, it appears that (1)
the nitrate additive is considered to be helpful in the initia-
tion step; (2) Selectfluor-derived species (such as 28) could
participate in the propagation step as a chain carrier,
though the efficiency of the propagation strongly depends
on the substrate used. The triple utility of Selectfluor as a
fluorine donor, mediator, and electrolyte is a rather memo-
rable aspect of this chemistry.
Finally, as the mechanisms for electrochemical and pho-
tochemical C–H fluorinations are radical based, a small
study was pursued to see if reactivity differences could be
observed with different medicinally relevant scaffolds. As
illustrated in Figure 1, substrates 24, 25, and 29 reacted
quite differently and in all cases showed superior reactivity
through the electrochemical mode. The origin of these dif-
ferences is not clear but points to the need for complemen-
tary new approaches to achieve this valuable transformation.
In summary, a simple and scalable protocol for the elec-
trochemical fluorination of unactivated C(sp3)–H bonds has
been developed. The scope has been explored across a
range of substrates bearing numerous types of functional
groups and the ease of scale-up is evidenced by the 100-
gram scale fluorination of a valine derivative. As electro-
chemical functionalization processes become more main-
stream, it is likely that this method will find use alongside
analogous C–H oxidation processes for both building-block
diversification and metabolic prediction.
Acknowledgment
The authors thank Dr. Jeremy T. Starr (Pfizer) for helpful discussions,
Prof. A. L. Rheingold (UC San Diego) for X-ray crystallographic analy-
sis, Dr. D.-H. Huang and Dr. L. Pasternack for assistance with NMR
spectroscopy, Dr. J. Chen for assistance with HRMS and SFC analyses,
and Dr. R. R. Merchant for assistance in the preparation of the manu-
script. We thank Enamine Ltd. for providing samples of several sub-
strates for fluorination. T.H. and T.S. would like to thank Mr. So Yasui
for NMR data collection and support with compounds 24, 25, and 26,
Dr. Hikaru Yoshimura for supporting chemistry on this work, and
Dr. Toshiki Kurokawa, Dr. Daiju Hasegawa, and Dr. Taro Terauchi for
helpful discussions.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611737.
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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strate (0.30 mmol), Selectfluor (A) (3.0 equiv, 319 mg, 0.90
mmol), NaNO3 (0.2 equiv, 5.1 mg, 0.06 mmol), and MeCN (3.0
mL). The vial cap equipped with a pair of RVC electrodes was
screwed on, and the headspace of the vial was purged with Ar
using a balloon, syringe and needle assembly prior to electroly-
sis. The reaction parameters of the ElectraSyn device were set
up as follows: constant current, 3.0 mA; no reference electrode;
total charge, 0.30 mmol substrate, ranging from 0.25 to 3.0
F/mol; alternate polarity, 2 min; stirring, 600 rpm. The mixture
was electrolyzed under Ar atmosphere until complete or rea-
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After electrolysis, the cap was removed, and the electrodes were
taken out and rinsed with MeCN into the reaction mixture. The
reaction mixture was poured into saturated aqueous NaHCO3
and extracted with CH2Cl2. The combined organics were
washed with brine, dried over anhydrous Na2SO4 and concen-
trated in vacuo. The crude material was purified by silica gel
column chromatography or preparative thin-layer chromatog-
raphy to furnish the desired product. See the Supporting Infor-
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E