Nucleophilic (Radio)Fluorination of Redox-Active Esters via Radical-Polar Crossover Enabled by Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.0c03125

We report a redox-neutral method for nucleophilic fluorination of N-hydroxyphthalimide esters using an Ir photocatalyst under visible light irradiation. The method provides access to a broad range of aliphatic fluorides, including primary, secondary, and tertiary benzylic fluorides as well as unactivated tertiary fluorides, that are typically inaccessible by nucleophilic fluorination due to competing elimination. In addition, we show that the decarboxylative fluorination conditions are readily adapted to radiofluorination with [¹⁸F]KF. We propose that the reactions proceed by two electron transfers between the Ir catalyst and redox-active ester substrate to afford a carbocation intermediate that undergoes subsequent trapping by fluoride. Examples of trapping with O- and C-centered nucleophiles and deoxyfluorination via N-hydroxyphthalimidoyl oxalates are also presented, suggesting that this approach may offer a general blueprint for affecting redox-neutral S_N1 substitutions under mild conditions.

Full text of DOI:10.1021/jacs.0c03125

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Article
Nucleophilic (Radio)Fluorination of Redox-Active Esters via Radical-
Polar Crossover Enabled by Photoredox Catalysis
Eric W. Webb, John B. Park, Erin L. Cole, David J. Donnelly, Samuel J. Bonacorsi, William R. Ewing,
and Abigail G. Doyle*
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ABSTRACT: We report a redox-neutral method for nucleophilic
fluorination of N-hydroxyphthalimide esters using an Ir photo-
catalyst under visible light irradiation. The method provides access
to a broad range of aliphatic fluorides, including primary,
secondary, and tertiary benzylic fluorides as well as unactivated
tertiary fluorides, that are typically inaccessible by nucleophilic
fluorination due to competing elimination. In addition, we show
that the decarboxylative fluorination conditions are readily adapted
to radiofluorination with [18F]KF. We propose that the reactions
proceed by two electron transfers between the Ir catalyst and
redox-active ester substrate to afford a carbocation intermediate
that undergoes subsequent trapping by fluoride. Examples of trapping with O- and C-centered nucleophiles and deoxyfluorination
via N-hydroxyphthalimidoyl oxalates are also presented, suggesting that this approach may offer a general blueprint for affecting
redox-neutral SN1 substitutions under mild conditions.
To overcome these limitations, researchers have recently
explored new strategies for carbocation generation under
nonacidic conditions. The Knowles group introduced a
methodology to access carbocation intermediates via mesolytic
cleavage following the oxidation of TEMPO-derived alkoxy-
amine substrates;8 although a wide range of nucleophiles are
compatible with this approach, the method was not shown to
work with fluoride and the substrates can be challenging to
access (Scheme 1C). Just recently, the Baran lab reported an
electrochemical approach to carbocation generation from
readily available carboxylic acids (Scheme 1D).9 The method
affords access to a broad range of hindered ethers from alcohol
nucleophiles and four examples of alkylfluorides from KF.
Although this report has significantly advanced the state of the
art, the requirement for oxidizing conditions places limits on
the substrate scope and the method was not shown to be
amenable to radiofluorination. This report was closely followed
by the disclosure of a photocatalytic decarboxylative ether
synthesis by Ohmiya, Nagao, and co-workers.10 Yet further
discovery and development of complementary methods for
carbocation generation are necessary to enable broad access to
INTRODUCTION
■
Aliphatic organofluorine compounds are important structural
motifs in pharmaceuticals, agrochemicals, and materials,
conferring valuable biological and physical properties.1 This
motif is also prominently featured in positron emission
tomography (PET) radiotracers.1a Consequently, the identi-
fication of mild methods for late-stage introduction of fluorine
has been a longstanding goal, with distinct strategies arising
using nucleophilic and electrophilic fluorine sources.2 For
reasons of cost, functional group compatibility, and translation
to radiofluorination, researchers have sought mild methods for
the preparation of fluoroalkyl groups using nucleophilic
fluoride.1,2 In most of these methods, Csp3−F bond formation
follows a bimolecular nucleophilic substitution pathway (SN2
mechanism) and is thus limited to the preparation of activated
or unhindered aliphatic fluorides (Scheme 1A).3 Indeed, the
typical restrictions on substrate scope for bimolecular
nucleophilic substitution reactions are even more acute for
fluoride due to its low nucleophilicity and high Brønsted
basicity, leading to competitive elimination.4,5
Stepwise nucleophilic fluorination reactions that proceed
through a carbocation intermediate (SN1 mechanism) provide
a complementary strategy to bimolecular alkyl fluoride
synthesis, enabling access to unactivated and hindered aliphatic
fluorides. However, the generation of carbocation intermedi-
ates typically requires harsh Brønsted6 or Lewis acidic
conditions7 that show poor functional group tolerance and
lead to elimination and rearrangement pathways (Scheme 1B).
Received: March 20, 2020
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© XXXX American Chemical Society
A

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to the construction of sterically congested ethers and C−C
bonds, establishing the generality of the strategy as a blueprint
for affecting redox-neutral SN1 substitutions. Finally, we show
that the method is amenable to 18F-radiofluorination.
Scheme 1. Nucleophilic Fluorination
RESULTS AND DISCUSSION
■
Optimization. We initiated our studies with the N-
hydroxyphthalimide ester 1 derived from naproxen, as
naproxen’s electron-rich arene would likely be incompatible
with decarboxylative fluorination conditions that utilize
electrophilic fluorine sources or stoichiometric oxidants.15b
Subjecting 1 to irradiation with 34 W blue LEDs in the
presence of 1 mol % Ir(dF-ppy)3 3 and 3 equiv of Et3N·3HF
delivered benzylic fluoride 2 in almost quantitative yield
(Table 1, entry 1). Fluorination does not proceed in the
a b
,
Table 1. Optimization of Reaction Conditions
hindered and unactivated aliphatic fluorides, including for late-
stage fluorination and radiofluorination, as well as expanding
the repertoire for additional synthetic applications.
In this context, we sought to develop a redox-neutral
method for carbocation generation via radical-polar cross-
over10,11 from N-hydroxyphthalimide esters (Scheme 1 E). We
selected redox active esters as a substrate class since numerous
research groups have recently reported their use as precursors
to alkyl radicals via single-electron reduction and decarbox-
ylation with release of a non-nucleophilic leaving group.12 We
hypothesized that upon single-electron reduction of the
substrate by the excited state of a suitable photoredox catalyst,
the resulting radical could be oxidized to the corresponding
carbocation by the oxidized photocatalyst and subsequently
trapped with fluoride.13 Given the similar trends in stability
between radical and carbocation species,14 we anticipated that
highly substituted aliphatic substrates should be particularly
amenable to both radical and carbocation generation in a
radical-polar crossover, thereby expanding the scope of
aliphatic fluorides available via nucleophilic fluorination. This
approach would also provide a useful complement to radical
methodologies for decarboxylative fluorination that require
oxidizing electrophilic fluorine sources15 or the combination of
a nucleophilic fluoride source with a stoichiometric oxidant, as
described by the Groves lab.16
a
b
0.2 mmol scale. All potentials given are versus a saturated calomel
c
electrode (SCE) and taken from ref 19. Yields determined by 19F-
NMR using 1-fluoronaphthalene as an external standard. General
conditions except 0.4 M, 1.5 equiv of Et3N·3HF. Isolated yield.
d
e
absence of light or photocatalyst, resulting in recovery of
starting material (Table 1, entries 2 and 3). More reducing or
oxidizing iridium photocatalysts were competent in the
reaction, as was the organic photocatalyst 4CzIPN, all
displaying high yet diminished reactivity compared to
photocatalyst 3 (Table 1, entries 4−6). While DCM was
found to be the optimal solvent for the reaction, fluorination
proceeded with moderate to good yield in tetrahydrofuran and
Here we report a redox-neutral decarboxylative nucleophilic
fluorination that delivers primary, secondary, and tertiary
benzylic fluorides and unactivated tertiary fluorides with broad
functional group tolerance. We also describe mechanistic
experiments that provide evidence for both radical and
carbocation intermediates; in so doing, we present applications
B
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a
Table 2. Substrate Scope for Photocatalytic Decarboxylative Fluorination
a
b
Isolated yields of an average of two runs on 0.5−1.0 mmol scale. Yield determined by 19F-NMR using 1-fluoronaphthalene as an external
c
d
e
f
standard. 1.3:1 d.r. >20:1 d.r. Product unstable. Yield corrected for starting material contamination with residual alcohol.
acetonitrile, solvents that are commonly used in radio-
fluorination (Table 1, entries 7 and 8). Only trace product
was observed using KF/HFIP (1,1,1,3,3,3-hexafluoro-
isopropanol)17 instead of Et3N·3HF, and no product was
observed using KF in the absence of HFIP (Table 1, entries 9
and 10). Although impractical from a preparative standpoint,
this result provides support for possible translation to
radiofluorination since [18F]KF is the most common reagent
for 18F-radiochemistry (vida infra).18 Finally, we found that the
reaction could be readily scaled to 4 mmol (Table 1, entry 11)
and photocatalyst loading could be reduced to 0.0625 mol %
with minimal impact on the reaction efficiency (Table 1, entry
12). This speaks to the practicality of the method, and the
ability to use such low photocatalyst loading holds important
mechanistic implications (vide infra).
tible to oxidation under previously reported decarboxylative
fluorination conditions were tolerated,15b delivering dioxole
15, benzyl-protected phenol 10, and thioether 11. Fluorinated
products bearing medicinally relevant amides and trifluor-
omethoxy groups were generated in good yields (12 and 13).
Whereas these electron-rich and electron-neutral primary
benzylic phthalimide esters were competent substrates,
electron-deficient substrates afforded benzylic fluorides in
low yield at high conversion (14), presumably because
single-electron reduction and decarboxylation to the carbon-
centered radical is facile but oxidation of the radical to the
cation is disfavored due to the electron-withdrawing
substituent.13 As expected on the basis of this hypothesis, we
found that replacing the primary benzylic substrate with a
secondary substrate bearing the same substitution pattern
restored reactivity, with fluorinated product 17 obtained in
93% yield.
Scope Elucidation. With optimized conditions in hand, we
evaluated the scope of the transformation. We found that a
variety of primary benzylic fluorides could be obtained in good
to excellent yields (Table 2, 7−13, 15, and 16). Several
substrates bearing electron-rich functionality otherwise suscep-
A common limitation in nucleophilic fluorination methods
that deliver secondary benzylic fluorides is elimination to
styrene byproducts.3d,f For all of the secondary substrates
C
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examined in Table 2, less than 5% elimination was observed, a
testament to the mildness of the conditions. Indeed, even
product 19 was obtained in high yield with minimal
elimination despite the presence of a β-carbonyl functional
group. By comparison, access to β-fluoro carbonyl derivatives
by deoxyfluorination has presented a major challenge to date
due to competing elimination.3d,f Several handles for
subsequent transition metal-mediated coupling were tolerated,
including aryl iodides 9, bromides 16 and 33, and chlorides 18
and 23−26. This tolerance for easily reduced functionality can
even be extended to azide-containing product 20, which was
generated in 56% yield and offers a reactive handle for
subsequent “click” chemistry that is widely used in
bioconjugation.21 Additionally, basic heterocycles and hetero-
aromatic groups otherwise susceptible to oxidation or Minisci
chemistry underwent decarboxylative fluorination in good
yields (18 and 26).
nucleophilic deoxyfluorination which is typically limited to
primary and secondary alcohols.3a−f
Mechanistic Investigations. We propose that excited 3
(E1/2* = −1.28 vs SCE19a) undergoes single-electron transfer
(SET) with the N-hydroxyphthalimide ester A (∼ −1.3 V vs
SCE20) (Figure 1). Fragmentation of the resulting phthalimide
In contrast to typical methods for nucleophilic fluorination,
we found that access to benzylic and unactivated tertiary
fluorides is possible. For example, acyclic 22 as well as tertiary
benzylic fluorides embedded within carbocyclic and hetero-
cyclic ring systems are generated in 70−92% yield, as in the
cases of 23−26. Likewise, both cyclic and acyclic unactivated
tertiary fluorides could be obtained (27−31). Whereas
neighboring group participation may be operative in the
generation of the homobenzylic tertiary fluorides 28 and 29, it
does not appear to be necessary given the success of the cyano-
substituted homobenzylic fluoride 29 and fluorides 27 and 31
that do not possess a proximal nucleophilic residue. Notably,
we were able to extend this protocol to the fluorination of
gemfibrozil 30 in 66% yield.
Fluoroether and fluorothioether functionality has been
shown to confer unique and valuable properties to biologically
active small molecules.22 We found that the redox-neutral
decarboxylative nucleophilic fluorination also delivers α-oxy-
and α-thioether motifs in moderate to good yield (32 and 33).
As a demonstration of the viability of the method for late-stage
derivatization, fluorinated ribose 34, trillipix-derivative 35, and
the herbicide cyhalofop-derived 36 were all readily accom-
modated. Likewise, application of the optimal conditions to the
preparation of difluoromethyl and perfluorinated groups was
successful,23 as in the cases of 37 and 38, and permitted the
synthesis of difluorofluorene 39, a motif featured in the
hepatitis C drug ledipasvir.
Fluorine incorporation is commonly used as a bioisostere for
several functionalities including C−OH and C−H bonds.1b In
this regard, the conversion of abundant alcohols into the
corresponding alkyl fluorides via deoxyfluorination represents
an attractive synthetic disconnection. However, deoxyfluorina-
tions of tertiary alcohols to access tertiary fluorides are typically
unsuccessful.24 MacMillan and co-workers have recently
reported a deoxyfluorination of oxalate half-esters to access
tertiary fluorides.25 However, the method uses an electrophilic
fluorine source. Since tert-alkyl N-hydroxyphthalimidoyl
oxalates are similar in redox potential to N-hydroxyphthalimide
esters, we hypothesized that these may be amenable to the
catalytic nucleophilic fluorination strategy outlined herein.26
Indeed, we were pleased to find that tertiary fluorides 22 and
40 could be obtained in 55% and 33% yield from tert-alkyl N-
hydroxyphthalimidoyl oxalate esters under otherwise identical
conditions. Since these substrates are readily available from
alcohols, the method represents a complementary approach to
Figure 1. Mechanistic proposal.
ester radical anion and subsequent extrusion of carbon dioxide
generate carbon-centered radical B. Radical intermediate B
ox
ox
(E1/2 = < 0.73 V vs SCE for 1° benzylic, E1/2 = 0.09 V vs
SCE for tertiary aliphatic13b) is then oxidized by photocatalyst
3+ (IrIV/IrIIIE1/2 = 0.94 V vs SCE19a), turning over the
photocatalyst and furnishing carbocation C. Finally, this
carbocation is trapped by the fluoride source to furnish the
desired alkyl fluoride D.
A number of experimental observations provide support for
the proposed mechanism. Stern−Volmer quenching analysis of
the individual components of the reaction mixture indicates
that the phthalimide ester quenches the excited state
photocatalyst with an observed KSV of 4.7 × 109 M−1 s−1,
which is similar to the quenching rate of the reaction
mixture.27 The quantum yield of this fluorination reaction is
0.37, indicating that chain mechanisms are unlikely or
inefficient.27,28 This result, combined with the observation
that the fluorinations proceed with high reaction efficiency at
extremely low photocatalyst loadings (0.0625 mol % of 3 in
Table 1, entry 12), suggests that the reaction is unimolecular in
photocatalyst.
Subjecting tertiary phthalimide ester 41 to the fluorination
conditions in the presence of several known radical traps
provides evidence for the intermediacy of a radical. For
example, addition of TEMPO (2,2,6,6-tetramethyl-1-piperidi-
nyloxy) to the reaction resulted in complete inhibition of
fluorination, with concomitant detection of TEMPO adduct 42
(Figure 2). In the presence of methyl acrylate, radical addition
product 43 was observed, along with a diminished yield of
tertiary fluoride 30 (66% isolated vs 45% by 19F NMR in the
presence of methyl acrylate). However, fluoride is not
incorporated into 43, presumably because radical oxidation
adjacent to the ester carbonyl is unfavorable. On the other
hand, conducting the fluorination reaction in the presence of
1.5 equiv of styrene afforded a new fluorinated product 44 in
addition to the direct fluorination product 30. 44 is most likely
D
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a
Table 3. Development of Radiochemical Protocol
a
Typical reaction conditions: 5.3 mol of 1, 16 mol % photocatalyst,
0.7 mL of MeCN, and [18F]F−/K2CO3/K222 (∼0.370 Gbq of activity
per reaction). RCC was determined by radio-TLC with number of
b
replicates noted.
alkyl sulfonates with [18F]KF in the presence of a phase
transfer reagent Kryptofix 2.2.2 (K222).18 As such, access to
high specific activity radiolabeled targets bearing unactivated
secondary or tertiary fluorides remains a critical challenge.
Moreover, the harsh conditions necessary for substitution of
even primary or activated secondary substrates (>100 °C and
high basicity) are often not suitable for late-stage radio-
fluorination and often lead to inseparable olefin byproducts.18
We anticipated that successful translation of the photocatalytic
decarboxylative nucleophilic fluorination method would there-
fore enable access to previously challenging or impossible to
prepare radiotracers.
To translate our method, we elected to pursue the
decarboxylative radiofluorination in acetonitrile to avoid any
potential clinical issues with dichloromethane. Testing the
radiofluorinations in CH3CN using [18F]KF/K222 as the
fluoride source, we found that the previously optimized
photocatalyst 3 was no longer the most effective, with Ir(F-
ppy)3 instead affording the highest radiochemical incorpo-
ration (Table 3, entries 1 and 4−7).27 No radiofluorination
was observed in the absence of light or photocatalyst as
determined by radio-TLC or radio-HPLC (Table 3, entries 2
and 3). While we had previously found that HFIP was
necessary for achieving fluorination using [19F]KF under the
nonradiochemical conditions (Table 1, entries 10 and 11), the
addition of HFIP proved detrimental in the radiochemical
system (Table 3, entry 9). Under the optimal conditions, the
reaction is particularly fast, furnishing [18F]2 in 62%
radiochemical conversion (RCC) within 2 min of irradiation
(Table 3, entry 8). The radiofluorination was also scalable
(1850−3700 MBq) albeit with diminished radiochemical
conversion, permitting generation of sufficient quantities of
[18F]2 to determine its molar activity (36.6 18.8 GBq/μmol,
decay corrected to end of synthesis), which is on par with
other no-carrier added nucleophilic fluorination proto-
cols.17,18,30 Notably, these radiochemical reactions were
conducted in a 3D-printed apparatus that permits automated
a
Figure 2. Radical and cation trapping. General conditions: 1 mol %
b
Ir(dF-ppy)3, 0.2 mmol of 41, 3 equiv of Et3N·3HF. 1.5 equiv of
TEMPO. c1.5 equiv of methyl acrylate. d1.5 equiv of styrene. e3 equiv
f
of 1,3,5-trimethoxybenzene and 0.3 equiv of Et3N·3HF. 5 equiv of
g
phenol and 0.3 equiv of Et3N·3HF. 6 equiv of methanol and 0.3
equiv of Et3N·3HF. 5 equiv of HFIP and run for 24 h; 19F NMR
h
yield vs external 1-fluoronaphthalene.
generated via addition of radical B to the styrene followed by
oxidation of the resulting benzylic radical and trapping with
fluoride. Evaluation of a series of electronically differentiated
styrene substrates, and the outcome of the reaction with
methyl acrylate, provides evidence against an alternative
pathway wherein radical oxidation to cation C precedes olefin
addition.27
As a test for the intermediacy of a carbocation, we
investigated whether other polar nucleophiles could be used
in the decarboxylative substitution reaction. Notably, we found
that C- and O-centered nucleophiles were competent with only
minor changes to the reaction parameters (Table 3, 45−48).29
For example, 1,3,5-trimethoxybenzene underwent addition to
generate benzhydryl 45 in 81% yield. This reaction represents
a Friedel−Crafts substitution without a Lewis acid using
abundant carboxylic acid precursors in place of alkyl halide
substrates. Likewise, several alcohol nucleophiles delivered
ether products 46−48 in good yield. The broad tolerance for a
range of nucleophiles, including sterically hindered and poorly
nucleophilic species, implicates the intermediacy of a
carbocation and demonstrates the generality of the strategy
to effect a range of challenging substitution reactions under
remarkably mild conditions.
Radiochemistry. Aliphatic 18F-radiolabeled PET tracers
are almost exclusively prepared by nucleophilic substitution of
E
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handling of radioactivity with irradiation taking place from the
bottom of the vials.27
Experimental procedures and characterization and
spectral data for new compounds (PDF)
Access to [18F]2 is significant since its synthesis by SN2
displacement with [18F]KF would likely be plagued by rapid
formation of elimination byproduct. We also briefly explored
application of the radiofluorination conditions to the radio-
synthesis of other fluorinated motifs that are challenging to
access using conventional methods (Table 4). For example, the
AUTHOR INFORMATION
Corresponding Author
■
Abigail G. Doyle − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0002-6641-0833; Email: agdoyle@
princeton.edu
Table 4. Scope of Photocatalyzed Radiofluorination
Authors
Eric W. Webb − Department of Chemistry, Princeton University,
Princeton, New Jersey 08544, United States
John B. Park − Department of Chemistry, Princeton University,
Princeton, New Jersey 08544, United States
Erin L. Cole − Discovery Chemistry Platforms, PET
Radiochemical Synthesis, Bristol-Myers Squibb Research and
Development, Princeton, New Jersey 08543, United States
David J. Donnelly − Discovery Chemistry Platforms, PET
Radiochemical Synthesis, Bristol-Myers Squibb Research and
Development, Princeton, New Jersey 08543, United States
Samuel J. Bonacorsi − Discovery Chemistry Platforms, PET
Radiochemical Synthesis, Bristol-Myers Squibb Research and
Development, Princeton, New Jersey 08543, United States
William R. Ewing − Discovery Chemistry, Bristol-Myers Squibb,
Princeton, New Jersey 08543-5400, United States
a
Typical reaction conditions: 5.3 mol of 1, 0.6 mg of Ir(F-ppy)3, 0.7
mL of MeCN, and [18F]F−/K2CO3/K222 (∼0.370 GBq of activity per
reaction). RCC was determined by radio-TLC with number of
replicates noted. Product identity was typically confirmed by HPLC
b
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c03125
coinjection. Reactions were conducted with 1.85−3.70 GBq of
c
activity per reaction. Reactions conducted using photocatalyst 3.
d
Product identity confirmed via TLC.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
radiofluorination protocol is amenable to the installation of a
tertiary fluoride: [18F]30 derived from gemfibrozil was
obtained in 9 2% RCC. Furthermore, we found that ribose
analogue [18F]34 could be prepared in 42% RCC. In this case,
the sulfonate precursor readily decomposes at room temper-
ature, severely limiting access to radiolabeled ribose analogues
by conventional substitution reactions.31
Financial support was generously provided by NSF (CHE-
1565983) and Bristol-Myers Squibb. We thank Dhar Murali
(BMS) for helpful suggestions, Erin E. Gomes (BMS) for
radiochemical and analytical expertise, and Daniel Batella
(BMS) for construction of the apparatus to allow radio-
́
chemical irradiation. Istvan Pelzer, Kenneth Conover, and John
Eng are acknowledged for analytical aid. We thank Laura K. G.
Ackermann, Meredith A. Borden, and Talia J. Steiman for
helpful discussions.
CONCLUSION
■
We have developed a photocatalytic method for nucleophilic
fluorination of N-hydroxyphthalimide esters that exploits the
redox activity of radicals as a route to carbocation formation.
The approach generates a variety of useful fluorinated motifs
under mild conditions and is compatible with functional
groups that challenge other synthetic methods using both
nucleophilic and electrophilic fluorine sources, such as access
to tertiary aliphatic fluorides and tolerance to electron-rich
functionality. Moreover, translation of the method to a
radiochemical protocol was possible, enabling radiofluorination
of derivatives of bioactive molecules. We present a preliminary
demonstration of the generality of this approach to redox-
neutral SN1-like substitutions in extensions to a new substrate
class, such as deoxyfluorination of tertiary N-hydroxyphthali-
midoyl oxalates, and to new nucleophiles, as in the
construction of sterically congested ethers and C−C bonds.
REFERENCES
■
(1) (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J.
Med. Chem. 2015, 58, 8315. (b) Jeschke, P. The Unique Role of
Fluorine in the Design of Active Ingredients for Modern Crop
Protection. ChemBioChem 2004, 5, 570. (c) Hagmann, W. K. The
Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008,
51, 4359.
(2) (a) Liang, T.; Neumann, C. N.; Ritter, T. Introduction of
Fluorine and Fluorine-Containing Functional Groups. Angew. Chem.,
Int. Ed. 2013, 52, 8214. (b) Neumann, C. N.; Ritter, T. Late-Stage
Fluorination: Fancy Novelty or Useful Tool? Angew. Chem., Int. Ed.
2015, 54, 3216.
(3) Deoxyfluorination with DAST: (a) Middleton, W. J. New
Fluorinating Reagents. Dialkylaminosulfur Fluorides. J. Org. Chem.
1975, 40, 574. (b) Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V.
Application of Dialkylaminosulfur Trifluorides in the Synthesis of
Fluoroorganic Compounds. Synthesis 1973, 1973, 787. Deoxyfluori-
nation with Phenofluor/Alkylfluor: (c) Tang, P.; Wang, W.; Ritter, T.
Deoxyfluorination of Phenols. J. Am. Chem. Soc. 2011, 133, 11482.
(d) Sladojevich, F.; Arlow, S. I.; Tang, P.; Ritter, T. Late-Stage
ASSOCIATED CONTENT
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Deoxyfluorination of Alcohols with Phenofluor. J. Am. Chem. Soc.
2013, 135, 2470. (e) Goldberg, N. W.; Shen, X.; Li, J.; Ritter, T.
AlkylFluor: Deoxyfluorination of Alcohols. Org. Lett. 2016, 18, 6102.
Deoxyfluorination with Pyfluor: (f) Nielsen, M. K.; Ugaz, C. R.; Li,
W.; Doyle, A. G. PyFluor: A Low-Cost, Stable, and Selective
Deoxyfluorination Reagent. J. Am. Chem. Soc. 2015, 137, 9571.
Fluorination with hypervalent iodine reagents: (g) Hara, S.;
Nakahigashi, J.; Ishi-i, K.; Sawaguchi, M.; Sakai, H.; Fukuhara, T.;
Yoneda, N. Difluorination of Alkenes with Iodotoluene Difluoride.
Synlett 1998, 1998, 495. (h) Chen, H.; Kaga, A.; Chiba, S. Anti-
Selective Aminofluorination of Alkenes with Amidines Mediated by
Hypervalent Iodine(III) Reagents. Org. Biomol. Chem. 2016, 14, 5481.
(i) Kong, W.; Feige, P.; De Haro, T.; Nevado, C. Regio- and
Enantioselective Aminofluorination of Alkenes. Angew. Chem., Int. Ed.
2013, 52, 2469. (j) Mennie, K. M.; Banik, S. M.; Reichert, E. C.;
Jacobsen, E. N. Catalytic Diastereo- and Enantioselective Fluoroami-
nation of Alkenes. J. Am. Chem. Soc. 2018, 140, 4797. (k) Banik, S.
M.; Medley, J. W.; Jacobsen, E. N. Catalytic, Asymmetric
Difluorination of Alkenes to Generate Difluoromethylated Stereo-
centers. Science 2016, 353, 51. (l) Banik, S. M.; Medley, J. W.;
Jacobsen, E. N. Catalytic, Diastereoselective 1,2-Di Fluorination of
Alkenes. J. Am. Chem. Soc. 2016, 138, 5000. Fluorination via ion-
binding catalysis: (m) Pupo, G.; Ibba, F.; Ascough, D. M. H. H.;
Vicini, A. C.; Ricci, P.; Christensen, K. E.; Pfeifer, L.; Morphy, J. R.;
Brown, J. M.; Paton, R. S.; Gouverneur, V. Asymmetric Nucleophilic
Fluorination under Hydrogen Bonding Phase-Transfer Catalysis.
Science 2018, 360, 638. (n) Pupo, G.; Vicini, A. C.; Ascough, D. M.
H.; Ibba, F.; Christensen, K. E.; Thompson, A. L.; Brown, J. M.;
Paton, R. S.; Gouverneur, V. Hydrogen Bonding Phase-Transfer
Catalysis with Potassium Fluoride: Enantioselective Synthesis of β-
Fluoroamines. J. Am. Chem. Soc. 2019, 141, 2878. (o) Pfeifer, L.;
Engle, K. M.; Pidgeon, G. W.; Sparkes, H. A.; Thompson, A. L.;
Brown, J. M.; Gouverneur, V. Hydrogen-Bonded Homoleptic
Fluoride-Diarylurea Complexes: Structure, Reactivity, and Coordinat-
ing Power. J. Am. Chem. Soc. 2016, 138, 13314.
(4) (a) Liang, S.; Hammond, G. B.; Xu, B. Hydrogen Bonding:
Regulator for Nucleophilic Fluorination. Chem. - Eur. J. 2017, 23,
17850. (b) Engle, K. M.; Pfeifer, L.; Pidgeon, G. W.; Giuffredi, G. T.;
Thompson, A. L.; Paton, R. S.; Brown, J. M.; Gouverneur, V.
Coordination Diversity in Hydrogen-Bonded Homoleptic Fluoride-
Alcohol Complexes Modulates Reactivity. Chem. Sci. 2015, 6, 5293.
(c) Nolte, C.; Ammer, J.; Mayr, H. Nucleofugality and Nucleophilicity
of Fluoride in Protic Solvents. J. Org. Chem. 2012, 77, 3325.
(d) Landini, D.; Maia, A.; Rampoldi, A. Dramatic Effect of the
Specific Solvation on the Reactivity of Quaternary Ammonium
Fluorides and Poly(Hydrogen Fluorides), (HF)n•F−, in Media of
Low Polarity. J. Org. Chem. 1989, 54, 328. (e) Lee, J.-W.; Oliveira, M.
T.; Jang, H. B.; Lee, S.; Chi, D. Y.; Kim, D. W.; Song, C. E. Hydrogen-
Bond Promoted Nucleophilic Fluorination: Concept, Mechanism and
Applications in Positron Emission Tomography. Chem. Soc. Rev. 2016,
45, 4638.
(7) Silver mediated fluorination: (a) Khotavivattana, T.; Verhoog, S.;
Tredwell, M.; Pfeifer, L.; Calderwood, S.; Wheelhouse, K.; Leecollier,
T.; Gouverneur, V. 18F-Labeling of Aryl-SCF3,-OCF3 and -OCHF2
with [18F]Fluoride. Angew. Chem., Int. Ed. 2015, 54, 9991.
(b) Verhoog, S.; Pfeifer, L.; Khotavivattana, T.; Calderwood, S.;
Collier, T. L.; Wheelhouse, K.; Tredwell, M.; Gouverneur, V. Silver-
Mediated 18F-Labeling of Aryl-CF3 and Aryl-CHF2 with 18F-Fluoride.
Synlett 2015, 27, 25. Boron trifluoride mediated fluorination and
references therein: (c) Cresswell, A. J.; Davies, S. G.; Roberts, P. M.;
Thomson, J. E. Beyond the Balz-Schiemann Reaction: The Utility of
Tetrafluoroborates and Boron Trifluoride as Nucleophilic Fluoride
Sources. Chem. Rev. 2015, 115, 566.
(8) Zhu, Q.; Gentry, E. C.; Knowles, R. R. Catalytic Carbocation
Generation Enabled by the Mesolytic Cleavage of Alkoxyamine
Radical Cations. Angew. Chem., Int. Ed. 2016, 55, 9969.
(9) Xiang, J.; Shang, M.; Kawamata, Y.; Lundberg, H.; Reisberg, S.
H.; Chen, M.; Mykhailiuk, P.; Beutner, G.; Collins, M. R.; Davies, A.;
Del Bel, M.; Gallego, G. M.; Spangler, J. E.; Starr, J.; Yang, S.;
Blackmond, D. G.; Baran, P. S. Hindered Dialkyl Ether Synthesis with
Electrogenerated Carbocations. Nature 2019, 573, 398.
(10) Shibutani, S.; Kodo, T.; Takeda, M.; Nagao, K.; Tokunaga, N.;
Sasaki, Y.; Ohmiya, H. Organophotoredox-Catalyzed Decarboxylative
C(sp3)-O Bond Formation. J. Am. Chem. Soc. 2020, 142, 1211.
(11) Atom transfer radical addition (ATRA) commonly invokes
radical oxidation by a photocatalyst: (a) Wallentin, C. J.; Nguyen, J.
D.; Finkbeiner, P.; Stephenson, C. R. J. Visible Light-Mediated Atom
Transfer Radical Addition via Oxidative and Reductive Quenching of
Photocatalysts. J. Am. Chem. Soc. 2012, 134, 8875. (b) Tlahuext-Aca,
A.; Garza-Sanchez, R. A.; Glorius, F. Multicomponent Oxyalkylation
of Styrenes Enabled by Hydrogen-Bond-Assisted Photoinduced
Electron Transfer. Angew. Chem., Int. Ed. 2017, 56 (13), 3708. For
a review of ATRA: (c) Courant, T.; Masson, G. Recent Progress in
Visible-Light Photoredox-Catalyzed Intermolecular 1,2-Difunctional-
ization of Double Bonds via an ATRA-Type Mechanism. J. Org. Chem.
2016, 81, 6945. ATRA-based fluorination: (d) Deng, W.; Feng, W.;
Li, Y.; Bao, H. Merging Visible-Light Photocatalysis and Transition-
Metal Catalysis in Three-Component Alkyl-Fluorination of Olefins
with a Fluoride Ion. Org. Lett. 2018, 20, 4245. For radical-polar
crossover to form anionic species: (e) Donabauer, K.; Maity, M.;
̈
Berger, A. L.; Huff, G. S.; Crespi, S.; Konig, B. Photocatalytic
Carbanion Generation-Benzylation of Aliphatic Aldehydes to
Secondary Alcohols. Chem. Sci. 2019, 10 (19), 5162.
(12) For a recent review of transformations using redox active esters,
see: Murarka, S. N-(Acyloxy)phthalimides as Redox-Active Esters in
Cross-Coupling Reactions. Adv. Synth. Catal. 2018, 360, 1735.
(13) (a) Wayner, D. D. M.; Houmam, A. Redox Properties of Free
Radicals. Acta Chem. Scand. 1998, 52, 377. (b) Wayner, D. D. M.;
McPhee, D. J.; Griller, D. Oxidation and Reduction Potentials of
Transient Free Radicals. J. Am. Chem. Soc. 1988, 110, 132.
(14) Anslyn, E.; Dougherty, D. A. Modern physical organic chemistry;
University Science Books: 2006.
(15) Silver-mediated decarboxylative fluorination with SelectfluorS:
(a) Yin, F.; Wang, Z.; Li, Z.; Li, C. Silver-Catalyzed Decarboxylative
Fluorination of Aliphatic Carboxylic Acids in Aqueous Solution. J. Am.
Chem. Soc. 2012, 134, 10401. Photomediated decarboxylative
fluorination with Selectfluoro and NFSI: (b) Leung, J. C. T.;
Chatalova-Sazepin, C.; West, J. G.; Rueda-Becerril, M.; Paquin, J. F.;
Sammis, G. M. Photo-fluorodecarboxylation of 2-Aryloxy and 2-Aryl
Carboxylic Acids. Angew. Chem., Int. Ed. 2012, 51, 10804.
Photoredox-mediated decarboxylative fluorination: (c) Rueda-
(5) Liotta, C. L.; Harris, H. P. The Chemistry of “Naked” Anions. I.
Reactions of the 18-Crown-6 Complex of Potassium Fluoride with
Organic Substrates in Aprotic Organic Solvents. J. Am. Chem. Soc.
1974, 96, 2250.
(6) (a) Olah, G. A.; Nojima, M.; Kerekes, I. Hydrofluorination of
Alkenes, Cyclopropane, and Alkynes with Poly-Hydrogen Fluoride/
Pyridine (Trialkylamine)Reagents. Synthesis 1973, 1973, 779.
(b) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes,
I.; Olah, J. A. Pyridinium Poly(Hydrogen Fluoride) (30% Pyridine-
70% Hydrogen Fluoride): A Convenient Reagent for Organic
Fluorination Reactions. J. Org. Chem. 1979, 44, 3872. (c) Lu, Z.;
Zeng, X.; Hammond, G. B.; Xu, B. Widely Applicable Hydro-
fluorination of Alkenes via Bifunctional Activation of Hydrogen
Fluoride. J. Am. Chem. Soc. 2017, 139, 18202. (d) Bertrand, X.;
Paquin, J.-F. Direct Hydrofluorination of Methallyl Alkenes Using a
Methanesulfonic Acid/Triethylamine Trihydrofluoride Combination.
Org. Lett. 2019, 21, 9759.
́
Becerril, M.; Mahe, O.; Drouin, M.; Majewski, M. B.; West, J. G.;
Wolf, M. O.; Sammis, G. M.; Paquin, J. F. Direct C-F Bond Formation
Using Photoredox Catalysis. J. Am. Chem. Soc. 2014, 136, 2637.
(d) Leung, J. C. T.; Sammis, G. M. Radical Decarboxylative
Fluorination of Aryloxyacetic Acids Using N-Fluorobenzenesulfoni-
mide and a Photosensitizer. Eur. J. Org. Chem. 2015, 2015, 2197.
(e) Ventre, S.; Petronijevic, F. R.; Macmillan, D. W. C.
Decarboxylative Fluorination of Aliphatic Carboxylic Acids via
Photoredox Catalysis. J. Am. Chem. Soc. 2015, 137, 5654. For
G
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
multi-fluorinated motifs, see: (f) Chatalova-Sazepin, C.; Binayeva, M.;
Epifanov, M.; Zhang, W.; Foth, P.; Amador, C.; Jagdeo, M.; Boswell,
B. R.; Sammis, G. M. Xenon Difluoride Mediated Fluorodecarbox-
ylations for the Syntheses of Di- and Trifluoromethoxyarene. Org.
Lett. 2016, 18, 4570. (g) Mizuta, S.; Stenhagen, I. S. R.; O’Duill, M.;
Wolstenhulme, J.; Kirjavainen, A. K.; Forsback, S. J.; Tredwell, M.;
Sandford, G.; Moore, P. R.; Huiban, M.; Luthra, S. K.; Passchier, J.;
Solin, O.; Gouverneur, V. Catalytic Decarboxylative Fluorination for
the Synthesis of Tri- and Difluoromethyl Arenes. Org. Lett. 2013, 15,
2648. (h) Wang, Z.; Guo, C. Y.; Yang, C.; Chen, J. P. Ag-Catalyzed
Chemoselective Decarboxylative Mono- and gem- Difluorination of
Malonic Acid Derivatives. J. Am. Chem. Soc. 2019, 141, 5617.
(16) (a) Huang, X.; Liu, W.; Hooker, J. M.; Groves, J. T. Targeted
Fluorination with the Fluoride Ion by Manganese-Catalyzed
Decarboxylation. Angew. Chem., Int. Ed. 2015, 54, 5241. For a
recent application of the methodology to the synthesis of multi-
fluorinated motifs: (b) Sap, J. B. I.; Wilson, T. C.; Kee, C. W.;
Straathof, N. J. W.; Ende, C. W. am; Mukherjee, P.; Zhang, L.;
Genicot, C.; Gouverneur, V. Synthesis of 18F-Difluoromethylarenes
Using Aryl Boronic Acids, Ethyl Bromofluoroacetate and [18F]-
Fluoride. Chem. Sci. 2019, 10, 3237.
Oxalates. J. Am. Chem. Soc. 2013, 135, 15342. (b) Lackner, G. L.;
Quasdorf, K. W.; Pratsch, G.; Overman, L. E. Fragment Coupling and
the Construction of Quaternary Carbons Using Tertiary Radicals
Generated from tert-Alkyl N-Phthalimidoyl Oxalates by Visible-Light
Photocatalysis. J. Org. Chem. 2015, 80, 6012.
(27) See Supporting Information for additional details and
discussion.
(28) Cismesia, M. A.; Yoon, T. P. Characterizing Chain Processes in
Visible Light Photoredox Catalysis. Chem. Sci. 2015, 6, 5426.
(29) An acidic additive was required in order to observe reactivity
with these alternative nucleophiles. No conversion was observed
without Et3N·3HF except in the case of sufficiently acidic HFIP.
(30) (a) Zlatopolskiy, B. D.; Zischler, J.; Krapf, P.; Zarrad, F.;
Urusova, E. A.; Kordys, E.; Endepols, H.; Neumaier, B. Copper-
Mediated Aromatic Radiofluorination Revisited: Efficient Production
of PET Tracers on a Preparative Scale. Chem. - Eur. J. 2015, 21, 5972.
(b) Jacobson, O.; Kiesewetter, D. O.; Chen, X. Fluorine-18
Radiochemistry, Labeling Strategies and Synthetic Routes. Bioconju-
gate Chem. 2015, 26, 1.
(31) D’Angelo, K. A.; Taylor, M. S. Borinic Acid Catalyzed Stereo-
and Regioselective Couplings of Glycosyl Methanesulfonates. J. Am.
Chem. Soc. 2016, 138, 11058.
(17) Gray, E. E.; Nielsen, M. K.; Choquette, K. A.; Kalow, J. A.;
Graham, T. J. A.; Doyle, A. G. Nucleophilic (Radio)Fluorination of α-
Diazocarbonyl Compounds Enabled by Copper-Catalyzed H-F
Insertion. J. Am. Chem. Soc. 2016, 138, 10802.
(18) (a) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Molecular
Imaging with PET. Chem. Rev. 2008, 108, 1501. (b) Cole, E.; Stewart,
M.; Littich, R.; Hoareau, R.; Scott, P. Radiosyntheses Using Fluorine-
18: The Art and Science of Late Stage Fluorination. Curr. Top. Med.
Chem. 2014, 14, 875−900. (c) Cai, L.; Lu, S.; Pike, V. W. Chemistry
with [18F]Fluoride Ion. Eur. J. Org. Chem. 2008, 2008, 2853−2873.
(d) Jacobson, O.; Kiesewetter, D. O.; Chen, X. Fluorine-18
Radiochemistry, Labeling Strategies and Synthetic Routes. Bioconju-
gate Chem. 2015, 26, 1−18. (e) Deng, X.; Rong, J.; Wang, L.; Vasdev,
N.; Zhang, L.; Josephson, L.; Liang, S. H. Chemistry for Positron
Emission Tomography: Recent Advances in 11 C-, 18 F-, 13 N-, and
15 O-Labeling Reactions. Angew. Chem., Int. Ed. 2019, 58, 2580−
2605. (f) Liang, S. H.; Vasdev, N. Total Radiosynthesis: Thinking
Outside ’the Box’. Aust. J. Chem. 2015, 68, 1319−1328.
(19) (a) Teegardin, K.; Day, J. I.; Chan, J.; Weaver, J. Advances in
Photocatalysis: A Microreview of Visible Light Mediated Ruthenium
and Iridium Catalyzed Organic Transformations. Org. Process Res. Dev.
2016, 20, 1156. (b) Speckmeier, E.; Fischer, T. G.; Zeitler, K. A
Toolbox Approach to Construct Broadly Applicable Metal-Free
Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox
Potentials and Importance of Halogens in Donor-Acceptor Cyanoar-
enes. J. Am. Chem. Soc. 2018, 140 (45), 15353.
(20) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M.
Photosensitized Decarboxylative Michael Addition through N-
(Acyloxy)Phthalimides via an Electron-Transfer Mechanism. J. Am.
Chem. Soc. 1991, 113, 9401.
(21) Boutureira, O.; Bernardes, G. J. L. Advances in Chemical
Protein Modification. Chem. Rev. 2015, 115, 2174.
(22) Shimizu, M.; Hiyama, T. Modern Synthetic Methods for
Fluorine-Substituted Target Molecules. Angew. Chem., Int. Ed. 2005,
44, 214.
(23) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.;
Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl Bioisostere:
Examining the “Lipophilic Hydrogen Bond Donor” Concept. J. Med.
Chem. 2017, 60 (2), 797−804.
(24) Nielsen, M. K.; Ahneman, D. T.; Riera, O.; Doyle, A. G.
Deoxyfluorination with Sulfonyl Fluorides: Navigating Reaction Space
with Machine Learning. J. Am. Chem. Soc. 2018, 140 (15), 5004.
́
́
(25) Gonzalez-Esguevillas, M.; Miro, J.; Jeffrey, J. L.; MacMillan, D.
W. C. Photoredox-catalyzed Deoxyfluorination of Activated Alcohols
with Selectfluor. Tetrahedron 2019, 75, 4222.
(26) (a) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. Direct
Construction of Quaternary Carbons from Tertiary Alcohols via
Photoredox-Catalyzed Fragmentation of tert-Alkyl N-Phthalimidoyl
H
https://dx.doi.org/10.1021/jacs.0c03125
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX