Predictable site-selective radical fluorination of tertiary ethers

Article abstract of DOI:10.1007/s11426-019-9636-8

In this communication, we disclose the first example of metal-free and site-selective radical fluorination of readily available tertiary alkyl ethers, enabled by synergistic photocatalysis and organocatalysis. This catalytic combination allows for exclusi

Full text of DOI:10.1007/s11426-019-9636-8

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https://doi.org/10.1007/s11426-019-9636-8
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Predictable site-selective radical fluorination of tertiary ethers
Junyang Ma, Wentao Xu & Jin Xie*
State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine
Innovation Center, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
Received October 5, 2019; accepted October 10, 2019; published online November 13, 2019
In this communication, we disclose the first example of metal-free and site-selective radical fluorination of readily available
tertiary alkyl ethers, enabled by synergistic photocatalysis and organocatalysis. This catalytic combination allows for exclusive
fluorination of tertiary C–O bonds under mild conditions even in the presence of competing reaction sites. The excellent
functional group tolerance affords valuable access to sterically hindered alkyl fluorides through late-stage modification of
complex molecules. The successful use of tertiary alkyl ethers in radical fluorination enhances the structural diversity of aliphatic
fluorides that can be derived from naturally abundant alcohols.
cooperative catalysis, C–O bond activation, radical fluorination, polarity-matching effect, umpolung
Citation:
Ma J, Xu W, Xie J. Predictable site-selective radical fluorination of tertiary ethers. Sci China Chem, 2019, 62, https://doi.org/10.1007/s11426-019-
9636-8
Fluorine, a small atom plays an important role in all fields of
science. For example, the fluorine atom has been recognized
as a bioisostere of the hydroxyl group [1]. In general, organo-
fluorine compounds are increasingly common in pharma-
ceuticals and agrochemicals (Scheme 1(a)) owing to their
unique physical and biological properties such as lipophili-
city, permeability and metabolic stability [2]. The develop-
ment of new strategies to construct C–F bonds has gained
considerable momentum in recent years [3].
Radical fluorination of alkyl radical precursors (Scheme 1
(b)) can afford a powerful route to tertiary aliphatic fluorine
compounds [4], which are a class of important substructures
in drugs (Scheme 1(a)). In the past decades, several readily
available aliphatic starting materials, such as alkyl car-
boxylic acids [5], alkyl boronates [6], alkyl halides [7] and
alkanes [8] have been successfully used in radical fluorina-
tion (Scheme 1(b)). Despite these advances, most of the
cases are mediated by transition metals and the precise
selectivity and the feasibility of late-stage modification in
radical fluorination remains challenging. A few methods of
radical fluorination originating from alcohols have been re-
ported during our preparation, but these methods indeed
undergo widely reported decarboxylation process [9]. Ali-
phatic ethers are readily available starting materials in or-
ganic synthesis [10] but the direct radical fluorination of
tertiary C–O bonds is unprecedented. The success of this
process will inarguably enhance the structural diversity of
aliphatic organic fluorides provided by the naturally abun-
dant precursor. In addition, photoredox catalysis is an
emerging strategy in organic synthesis [11]. Herein, we re-
port the first site-selective radical fluorination of tertiary
ethers under metal-free conditions. Commercially available
Selectfluor was used as the fluorination reagent and the re-
action proceeds by means of synergistic photocatalysis and
organocatalysis. This new protocol can be applied to late-
stage monofluorination of complex pharmaceutical analo-
gues with excellent regioselectivity and functional group
compatibility and, for substrates bearing competing reaction
sites, controllable radical fluorination can be achieved pre-
dictably.
*Corresponding author (email: xie@nju.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019
chem.scichina.com link.springer.com

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Ma et al. Sci China Chem
Scheme 2 Mechanistic hypothesis (radical chain pathway was added:
path B) (color online).
was equipped with nitrogen. Then MeCN (3.0 mL), 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN) (12.4 mg, 0.1 mmol)
and 1-(4-(2-(methoxymethoxy)propan-2-yl)phenyl) ethan-1-
one (1a) (44.5 mg, 0.2 mmol) were added in sequence under
N2 atmosphere. The reaction mixture was stirred under the
irradiation of 45 W blue light-emitting diodes (LEDs, dis-
tance app. 10.0 cm from the bulb) at room temperature for
12 h. When the reaction finished, the mixture was quenched
with water and extracted with ethyl acetate (3×10 mL). The
organic layers were combined and concentrated in vacuo.
The product was purified by flash column chromatography
on silica gel (petroleum ether:ethyl acetate, 20:1) and
27.0 mg product 1-(4-(2-fluoropropan-2-yl)phenyl) ethan-1-
one (3a) was obtained in 75% yield.
A model reaction to investigate the reaction conditions, 1a
with Selectfluor was selected. Although direct nucleophilic
deoxyfluorination of alcohols with diethylaminosulfur tri-
fluoride (DAST) [16], PhenoFluor [17], PyFluor [18], or
SulfoxFluor [19] is workable, these methods usually have the
disadvantage of limited functional group tolerance. The
success of the radical fluorination of 1a can further
strengthen its synthetic value. To initiate the C–O bond
cleavage, a suitable hydrogen-atom transfer co-catalyst is
necessary. However, the initial use of thiols as HAT catalysts
only gave moderate yields (see Supporting Information on-
line for details). We speculated that the HAT ability of thiols
was insufficient because of the moderate bond dissociation
energy (BDE). In the light of recent literatures [12,20], we
focused on tertiary amines, another class of frequently-used
HAT catalysts and found that DBN was a suitable HAT
catalyst. As shown in Table 1, under the optimized reaction
conditions (entry 1), the target product (3a) was obtained
from 1a in 81% gas chromatography (GC) yield. The use of
other photocatalysts (2b–2d) in place of 2a resulted in lower
yields (entries 2–4). The screening of HAT catalysts showed
that DBN could give a better result (entries 5–7) and the
amount of DBN could significantly influence the reaction
Scheme 1 The prevalence of tertiary alkyl fluorides in bioactive com-
pounds and general radical fluorination strategies (color online).
To achieve a reaction site with precision, a hydrogen atom
transfer (HAT) catalyst can be used because it usually plays a
crucial role in generating the corresponding alkyl radical. An
excessively strong HAT ability will decrease the regios-
electivity while too weak ability will result in failure [12].
Based on our recent investigations, the HAT process can be
tuned by the use of suitable kinds of HAT catalysts, typically
thoils or tertiary amines [12,13]. A plausible mechanistic
pathway for a possible catalytic cycle is proposed in Scheme
2. Under the irradiation of visible-light, the photo-excited
photocatalyst with a high oxidation potential [e.g., Arc-Mes-
Me+* [1/2E(Arc-Mes-Me+*/Arc-Mes-Me)]=2.06 V vs. SCE]
can undergo a single electron oxidation of the hydrogen-
atom transfer catalyst to give the radical cation (I). This can
go through a rapid polarity-matched HAT process with the
hydridic C–H of the tertiary ether (1) to form the alkoxyl
radical (II). Subsequently, C–O homolysis of alkoxyl radical
(II) generates the tertiary alkyl radical (III), with the release
1
of methyl formate (identified by H NMR, see Supporting
Information online for details). The resulting nucleophilic
tertiary alkyl radical immediately attracts a fluorine atom
from Selectfluor to produce the corresponding tertiary
fluorides (3) [14]. Finally, the generated radical cation (V)
accepts an electron, completing the photoredox cycle. On the
other hand, since V has the similar radical cation structure
with I, it may trigger analogous HAT process [15], which
leads to a radical chain pathway to generate target product 3
(path B).
Selectfluor (212.5 mg, 0.6 mmol) and 9-mesityl-10-me-
thylacridin-10-ium perchlorate (2a) (1.7 mg, 0.004 mmol)
were placed in a 4 mL transparent vial equipped with a
stirring bar. Then the vial was carried into glovebox which

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Ma et al. Sci China Chem
a)
Table 1 Optimization of the reaction conditions
b)
Entry
1
Variation of standard conditions
Yield (%)
None
81 (75)
22
7
2
2b instead of 2a
2c instead of 2a
2d instead of 2a
3
4
19
56
56
18
23
46
24
10
0
c)
5
DBU instead of DBN
6
Quinuclidine instead of DBN
7
N-phenylmethanesulfonamide instead of DBN
8
1 equiv. DBN
0.1 equiv. DBN
No DBN
9
10
11
12
No photocatalyst
Dark
a) Standard conditions: 1a (0.2 mmol), 2a (2 mol%), DBN (50 mol%),
Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis
(tetrafluoroborate), 3 equiv.), MeCN (3 mL), blue LEDs, room temperature,
12 h. b) Measured by GC using acetophenone as internal standard. The
isolated yield was given in the parentheses. c) DBU=1,8-diazabicyclo
[5.4.0] undec-7-ene.
Scheme 3 Scope of the ethers in 0.2 mmol scale (yields of isolated
products are given) (color online).
general, the protocol can achieve exclusive radical fluor-
ination of a wide series of tertiary alkyl ethers with excellent
functional group tolerance. Benzylic tertiary ethers can be
converted to the corresponding tertiary fluorides in moderate
to good yields (3a–3d). Alkyl ethers containing weak
C(sp3)–H bonds (e.g., benzylic C–H bonds or the α-C–H of a
heteroatom) are also competent substrate partners and give
predictable site-selectivity products (3e–3dd). Various elec-
tron-withdrawing and -donating substituents on phenyl rings
are well tolerated, furnishing the desired tertiary aliphatic
fluorides (3h–3s) in satisfactory yields of up to 97%. This
new protocol exhibits excellent functional group compat-
ibility, involving ketones (3p, 3t, 3u), aldehydes (3o), bor-
onates (3l), phthalimides (3cc), iodo (3n) as well as nitro (3r)
and heteroaryl groups (3z, 3aa, 3dd), further increasing its
synthetic value. Importantly, the success of radical fluor-
ination of the pinyl borate-substituted ether (3l) is com-
plementary to deboronofluorination and can facilitate
downstream transformations.
yield (entries 8–10). We envisioned that DBN had two
possible roles, as an HAT catalyst and as an organic base
which facilitates the deprotonation of [H-cat]+ species. In the
absence of DBN, a 24% yield of the desired product was
delivered (entry 10). The reason for this is the generated
tertiary ammonium radical cation from Selectfluor reagents
as an alternative HAT catalyst during the reaction. In addi-
tion, we have tested other products, such as 3p and 3ee. In the
absence of DBN, only a small amount of the desired product
could be formed (see Supporting Information online for
details). A 10% yield of product was also obtained for the
model reaction in the absence of a photocatalyst (entry 11).
We speculate that nitrogen-fluorine halogen bonding [21]
might exist between DBN and Selectfluor and that the non-
covalent compounds could be somewhat excited by visible
light (see Supporting Information online for details).
Therefore, to a certain extent the further increase of DBN to
1 equiv., leading to a decreased yield (entry 8) can be ra-
tionalized due to the consumption of Selectfluor via nitro-
gen-fluorine halogen bonding.
To demonstrate the synthetic robustness of this radical
fluorination of ethers, we applied it to late-stage fluorination
(Scheme 4). We found that it was very efficient and site-
selective, accomplishing radical fluorination of tertiary C–O
With the optimized reaction conditions in hand, we in-
vestigated the reaction scope of tertiary ethers (Scheme 3). In

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Ma et al. Sci China Chem
Scheme 5 Consecutive procedures for C–O bond radical fluorination of
complex tertiary alcohols (color online).
Scheme 4 Late-stage modification of complex molecules. See Supporting
Information online for details of conditions (color online).
bonds in complex molecules. A series of derivatives of
biologically important compounds, containing alkynes, tet-
razoles, pyrimidines or strained rings successfully deliver the
desired sterically hindered alkyl fluorides (4a–4f). This il-
lustrates the generality of the synthetic methodology.
To further demonstrate the practicality of our protocol, the
radical fluorination of ethers was applied to fluorination of
the corresponding alcohols via a consecutive synthetic
pathway (Scheme 5). After the treatment of tertiary alcohols
(5 and 6) with chloromethyl methyl ether (MOMCl), the
resulting MOM-type ethers could be directly used for the
radical fluorination in moderate yields without further pur-
ification. In comparison, the target fluorination products
could not be obtained when treating the tertiary alcohols with
DAST (see Supporting Information online for details). This
synthetic route generates tertiary alkyl fluorides from tertiary
alcohols, with better functional group compatibility than the
classical methodology using DAST.
A series of control experiments were performed to gain
insight into the mechanism of this reaction. It was found that
addition of radical trapping reagents (TEMPO (2,2,6,6-tet-
ramethylpiperidinyloxy) and BHT (2,6-di-tert-butyl-4-me-
thylphenol)) to the reaction of 1a sharply decreased the yield
of 3a, indicating that a free radical process might be involved
(Scheme 6(a)). The radical clock experiment further con-
firmed this possibility (Scheme 6(b)). In addition, a lumi-
nescence quenching experimental result demonstrated that
the photocatalyst was quenched by DBN (Scheme 6(c)),
supporting the proposed HATcatalytic pathway in Scheme 2.
The quantum yield of the reaction was measured to be 0.7,
which indicated that a short radical chain pathway was
Scheme 6 The mechanistic investigation. (a) Radical inhibition experi-
ments; (b) radical-clock experiments; (c) luminescence quenching experi-
ments (color online).
possible. The use of radical initiator 2,2′-azobis(2-methyl-
pro-pionitrile) (AIBN) could trigger the reaction in 16%
yield (see Supporting Information online for details), sug-
gesting the possibility of radical chain pathway.
In conclusion, we have developed a predictable site-se-
lective radical fluorination of tertiary ethers under metal-free
conditions by means of synergistic photoredox catalysis and
organocatalysis. This unprecedented protocol allows for
excellent functional group compatibility and site-selectivity.
Its synthetic robustness is illustrated by late-stage fluorina-
tion of complex drug analogs and radical fluorination of
tertiary alcohols by consecutive one-pot operation. This ra-
dical fluorination provides a new access to tertiary alkyl
fluorides from readily available ethers as a new radical

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Ma et al. Sci China Chem
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Acknowledgements This work was supported by the National Natural
Science Foundation of China (21971108, 21702098), the Natural Science
Foundation of Jiangsu Province (BK20190006), Fundamental Research
Funds for the Central Universities (020514380176), “Jiangsu Six Peak
Talent Project”, “1000-Youth Talents Plan’’, and start-up funds from
Nanjing University. Mr. Xu was supported by the Scientific Research
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