Synthesis of Alkyl Fluorides by Silver-Catalyzed Radical Decarboxylative Fluorination of Cesium Oxalates

Article abstract of DOI:10.1002/ejoc.202100344

A combination of silver nitrate (AgNO₃) catalyst and Selectfluor was found to perform radical deoxyfluorination of cesium oxalates derived from corresponding alcohols. The reaction tolerates a wide range of functional groups and provides preferentially access to tertiary alkyl fluorides.

Full text of DOI:10.1002/ejoc.202100344

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doi.org/10.1002/ejoc.202100344
Synthesis of Alkyl Fluorides by Silver-Catalyzed Radical
Decarboxylative Fluorination of Cesium Oxalates
Émilie Vincent[a] and Julien Brioche*[a]
A combination of silver nitrate (AgNO3) catalyst and Selectfluor®
was found to perform radical deoxyfluorination of cesium
oxalates derived from corresponding alcohols. The reaction
tolerates a wide range of functional groups and provides
preferentially access to tertiary alkyl fluorides.
Introduction
Fluorine substitution is continuously explored in the context of
drug development since it usually allows to modulate the
properties of a drug candidate (e.g. conformation, lipophilicity
and pKa) as well as to improve its metabolic stability.[1] This
prominent role of fluorine in medicinal chemistry and the
demand for efficient fluorination methods have stimulated the
field of fluorine chemistry for decades. Accordingly, numerous
synthetic tools have been reported for the preparation of both
aromatic[2] and aliphatic fluorides.[3] Recent surveys of a large
number of marketed fluoro-pharmaceuticals clearly show that
drugs containing aromatic fluorine substitution are more
common than those featuring fluorine atoms in their aliphatic
regions.[4] The rather challenging synthesis of aliphatic fluorides
probably reflects the reason of the lack of presence of such
molecules in the landscape of fluorinated drugs. Therefore, the
development of new efficient and site-selective aliphatic
fluorination methods of complex molecules remains highly
desirable.
In this context, radical fluorination reactions[5,6] have
emerged as valuable and complementary synthetic tools for the
preparation of aliphatic fluorides A compared to well estab-
lished electrophilic, nucleophilic or transition metal-catalyzed
fluorination transformations.[7] Conceptually, radical fluorination
reactions rely on initiating a single electron transfer (SET)
Scheme 1. a. General concept of radical fluorination and main fluorination
reagents used in such transformations; b. Visible-light-mediated formal
radical deoxyfluorination of alcohols. PC=Photo-Catalyst. HATC=Hydrogen
Atom Transfer Catalyst.
process from an appropriate substrate under
a specific
activation mode (e.g. thermal, chemical, electrochemical or
photochemical) to generate an alkyl radical B. The latter
subsequently participates into a fluorine atom transfer (FAT)
with a radicophile fluorine source [e.g. N-fluoropyridinium salts
(NFPy’s), N-fluorobenzensulfonimide (NFSI), Selectfluor® and N-
fluoro-N-arylsulfonamide (NFAS)], resulting in the formation of a
C(sp3)À F bond (Scheme 1a).
preparation of alkyl fluorides A by a formal radical deoxyfluori-
nation reaction of alcohols C has recently received substantial
attention from several groups, including ours. To this matter,
oxalate half ester salts D[8c,d,f,g] and methoxymethyl ethers E,[8k]
both readily available from alcohols, have been employed as
alkyl radical precursors in the presence of Selectfluor® to
produce alkyl fluorides (Scheme 1b). The key C-centered radical
B intermediates were generated under visible-light-mediated
conditions via the homolytic C(sp3)À O bond cleavage triggered
by an oxidative double decarboxylation process and by a
hydrogen atom transfer (HAT), respectively. Such a transforma-
tion showed a real synthetic potential for the preparation of
alkyl fluorides under mild conditions. Particularly, the reported
Among the numerous radical fluorination transformations
which have been reported for the past decade,[8–12] the
[a] É. Vincent, Dr. J. Brioche
INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014)
Normandie University
76000 Rouen, France
E-mail: julien.brioche@univ-rouen.fr
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100344
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methods were found to efficiently provide access to tertiary
oxidizing agent while also being a radicophile fluorine atom
source in such radical decarboxylative fluorination method.
Inspired by the studies mentioned above, we thus surmised
that radical deoxyfluorination of oxalate half ester cesium salts
D could also be performed in the presence of a silver-based
alkyl fluorides compared to nucleophilic deoxyfluorination
reactions of tertiary alcohols which usually lack of efficiency and
suffer from the formation of olefinic side-products.[13] However,
from a practical point of view, a potential limitation of these
fluorination methods remains the use either of a rare transition
metal photocatalyst and/or of visible-light which could be
deleterious to photosensitive substrates.
catalyst and Selectfluor® to delivered alkyl fluorides
A
(Scheme 2d). We report herein our findings regarding this work
hypothesis.
Therefore, the development of a non-visible-light-mediated
alternate protocol to perform the aforementioned radical
deoxyfluorination reaction would further extend its application Results and Discussion
in organic synthesis. With this aim in mind, we kept on
investigating the radical deoxyfluorination of oxalate deriva-
tives. Although such alkyl radical precursors have been
Focusing our efforts on the rather challenging synthesis of
tertiary alkyl fluorides,[20] oxalate half ester cesium salt 2a was
selected as a model substrate (Table 1). Building on our
previous study, 2a was generated upon hydrolysis of its
successfully
used
in
various
visible-light-mediated
transformations,[14,15] they have long been known to undergo
°
non-light-mediated
radical
decarboxylative
precursor methyl oxalate 1a at 0 C in the presence of cesium
transformations.[14k,16,17]
hydroxide (CsOH) (1.05 equiv.) in an acetone:water (1.2:1)
mixture as solvent. Subsequent radical fluorination reaction of
2a was carried out in the same pot. Optimal conditions for this
step were obtained using AgNO3 catalyst (5 mol%) in the
presence of Selectfluor® (2.0 equiv.) at room temperature and in
the dark, thus generating 3a in 74% yield (entry 1). A two-fold
increase of the reaction’s dilution did not have a significant
impact on the output of the reaction (entry 2). Only traces of 3a
were observed by 19F NMR analysis of the crude reaction
mixtures either in the absence of AgNO3 (entry 3) or when the
radical deoxyfluorination was directly performed from methyl
oxalate 1a (entry 4). Finally, the use of other silver-based
catalysts such as AgBF4 (entry 5) of Ag2CO3 (entry 6) did not
improve the yield.
More specifically, studies reported by Minisci regarding
radical alkylation of N-heterocyclic or quinone derivatives drew
our attention (Scheme 2a and Scheme 2b).[16b,c] In these cases,
the oxidative decarboxylation process leading to alkyl radical
intermediates from oxalic acid half esters E was promoted by a
combination of silver nitrate (AgNO3) catalyst and sodium
persulfate (Na2S2O8) as stoichiometric oxidizing agent. Yet, a
recent mechanistic study carried out by the Flowers’ group[18]
on the silver-catalyzed radical decarboxylative fluorination of
carboxylic acids originally reported by Li,[19] has demonstrated
that Selectfluor® could be replaced by a combination of sodium
persulfate and NFSI (Scheme 2c) to produce alkyl fluorides.
These results strongly suggest that Selectfluor® is acting as an
With the optimized conditions in hand, the scope of the
radical decarboxylative fluorination of cesium oxalate deriva-
tives 2 was investigated (Scheme 3). First, the tandem sequen-
tial hydrolysis/radical fluorination protocol was applied to a
range of methyl oxalates 1b–1o derived from tertiary alcohols.
In most cases, tertiary aliphatic fluorides were isolated in
satisfactory yields (3b–3o, 34–95%). A variety of functional
groups including tosylate (3b), azide (3c), phtalimide (3d),
nitrile (3e), ester (3f, 3h and 3o), alcohol (3g), ketone (3k and
3m), dienone (3n) and acetonide (3o) were tolerated under the
Table 1. Optimization of the reaction conditions.[a]
Entry
Deviation from above conditions
Yield [%][b]
1
2
3
4
5
6
None
74
73
trace
trace
74
0.05 M instead of 0.1 M
Basic hydrolysis of 1a not performed
No AgNO3
AgBF4 instead of AgNO3
Ag2CO3 instead of AgNO3
74
Scheme 2. Silver-catalyzed radical decarboxylative functionalizations.
[a] All reactions were conducted on 0.25 mmol scale. [b] Isolated yields.
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selectivity. Finally, the practical utility of the developed
fluorination protocol was demonstrated by conducting experi-
ments on gram-scale, delivering fluorides 3k and 3o in 74%
and 42% yield, respectively.
The moderate yield observed for the hydrolysis/radical
fluorination sequence using furanosyl derived methyl oxalate
1o can be explained by the formation, during the reaction, of
its alcohol precursor (isolated back in 27% yield) and of several
uncharacterized fluorinated side-products. In this case, the
overall electronic withdrawing effect of the furanosyl ring onto
the methyl oxalate moiety seems to compete with the steric
effect at the 3’ position, thus allowing the hydrolysis to take
place at the alternate carbonyl moiety of the ester prior to the
fluorination step. In view of limiting this competing side-
reaction, an attempt was made to carry out the radical
fluorination transformation without CsOH from oxalic acid
monoester 1’o. In this case, the fluorinated side-products were
still observed but the formation of the alcohol precursor was
significantly limited and the desired fluoride 3o could be
isolated in a moderately improved 55% yield.
Next, the scope of the fluorination protocol was briefly
investigated with secondary and primary cesium oxalates. The
latter were generated in situ from oxalic acids 1p–1u after a
simple acid/base reaction in the presence of CsOH and
subsequently submitted to radical fluorination conditions in the
same pot with 20 mol% of AgNO3. Despite full conversions, all
reactions were found to be less clean and the desired fluorides
were only isolated in poor to moderate yields (3p–3u, 4–64%).
1
Careful examination of H NMR spectra of the crude reaction
mixtures indicated the presence of alcohol precursors only for
the reactions run from oxalic acids 1u and 1v. In the first case,
the yield of 3u could be slightly improved from 4% to 18% by
running the fluorination transformation without base. On the
other hand, 1H and 19F NMR analysis of the crude mixture
carried out with the substrate 1v indicated, respectively, that
the alcohol precursor was the main product and no trace of the
desired fluoride could be detected. Similar observations were
made even by carrying the reaction without CsOH. Overall,
these results clearly indicate the superiority of our fluorination
protocol towards tertiary fluorides.
By analogy to the well-studied mechanism of Ag-catalyzed
decarboxylative radical fluorination of carboxylic acids in the
presence of Selectfluor®,[18,21] the following mechanism is
proposed for the reported Ag-catalyzed radical deoxyfluorina-
tion of oxalates (Scheme 4).
Scheme 3. Scope of the silver-catalyzed radical decarboxylative fluorination
of oxalates. Isolated Yield. [a] AgNO3 (5 mol%). [b] AgNO3 (20 mol%). [c] Run
on gram-scale. [d] Run without CsOH and from oxalic acid (1; R = H). [e]
Diastereoisomeric ratio determined by 19F NMR analysis of the crude reaction
mixture. [f] Yield determined by 19F NMR analysis using 3,5-bis
(trifluoromethyl)bromobenzene as internal standard.
reaction conditions. The radical fluorination process was found
to be compatible with the presence of electron-poor or -neutral
aromatic substituents at the transient C-centered radical
affording fluorides 3h and 3i in 78% and 67% yield. However,
the presence of a benzyl substituent was found to have a
deleterious effect on the reaction delivering the desired product
3j in only 34% yield.
The reaction conditions were further applied to methyl
oxalates derived from the natural product cedrol and from
molecules of biological interest such as steroids or carbohy-
drates. In these cases, the corresponding fluorides (3l–3o) were
obtained in moderate to good yields and with high levels of
First, cesium oxalate 2 reacts with Ag(I) catalyst to generate
Ag(I)-carboxylate 4. Subsequent single-electron oxidation of 4
by Selectfluor® provides radical cation 5 and Ag(II)-carboxylate
6. Then, homolytic cleavage of the OÀ Ag(II) bond triggers the
decarboxylation process to regenerate Ag(I) catalyst and to give
successively alkoxycarbonyl 7 and C-centered 8 radicals. The
latter participates in a fluorine atom transfer with Selectfluor® to
give to the alkyl fluoride product 3 and radical cation 5.[22] The
latter, can alternatively oxidize Ag-(I) to Ag-(II) to pursue the
catalytic cycle.
To support the above proposed mechanism, the radical
nature of the fluorination process was first examined. Using our
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At this stage, the role of Selectfluor® in our fluorination
protocol was briefly investigated by carrying out a series of
controlled experiments. First, NFSI which is known to be a
weaker oxidant than Selectfluror® (E(NFSI) =À 0.78 V vs. SHE and
E
(Selectfluror®) =À 0.04 V vs. SHE),[23] was used in our optimized
conditions as sole fluorine atom source (Scheme 6, eq. 1). In this
case, the desired fluoride 3a was not observed in the crude
reaction mixture by 19F NMR analysis. However, when the
reaction was performed with NFSI and in the presence Na2S2O8
(0.5 equiv.) as an additional oxidant, the fluorination reaction
took place again albeit 3a was isolated in 18% yield (Scheme 6,
eq. 2). These results are in agreement with those described in
the mechanistic study of the Flowers’ group[18] regarding the
radical decarboxylative fluorination of carboxylic acid. Thus,
Selectfluor® is also likely to be involved in both oxidation of
Ag(I) into Ag(II) and fluorine atom transfer with the alkyl radical
intermediate in the radical decarboxylative fluorination of
oxalates.
Finally, to illustrate that our fluorination protocol can be
incorporated into the synthetic strategy towards a molecule of
biological interest, we briefly examined the preparation of a
fluoro-nucleoside analogue.[24] Thus, fluoro-ribofuranose 3o was
converted into the corresponding protected 3’-fluoro-3’-meth-
ylnucleoside 13 via a classic three steps reaction sequence (not
optimized). As outlined in Scheme 7, initial cleavage of the
acetonide (HCO2H, H2O) followed by acetylation of the transient
1,2-diol (Ac2O, Pyridine) gave the 1,2-diacetate 12 in 74% yield
and as a 2:1/α:β anomeric mixture. Introduction of thymine
under the Vorbrüggen conditions[25] provided the desired
nucleoside 13 in moderate yield (48%, 68% brsm) and with
great diastereoselectivity (d.r. >95:5).
Scheme 4. Proposed mechanism.
optimized conditions, an initial experiment was carried out in
the presence of TEMPO (1.0 equiv.) as radical scavenger. In this
case, the transformation was found to be significantly inhibited.
Indeed, fluoride 3a could only be observed in traces amount in
the 19F crude spectra and TEMPO adduct 9 was isolated in 25%
yield (Scheme 5, eq. 1). Furthermore, careful purification of the
crude reaction mixture resulting from the radical fluorination of
cesium oxalate 2t allowed us to isolate the reduced side-
product 10 in 22% yield alongside the desired product 3t
(Scheme 5, eq. 2). Thus, the formation of both 10 and 3t could
be explained by a competition between a HAT and a FAT
involving alkyl radical 11 and presumably a molecule of solvent
and Selectfluor®, respectively (Scheme 5, eq. 2). Overall, these
experimental results strongly support both alkoxycarbonyl 7
and alkyl 8 radical intermediates mentioned in the proposed
mechanism.
Scheme 6. Role of Selectfluor® in the reported fluorination reaction
Scheme 7. Preparation of 3’-fluoro-3’-methylnucelosides: (a) HCO2H, H2O; (b)
Ac2O, pyridine, 74% over two steps; c) Thymine, BSA=N,O-bis(trimethylsilyl)
acetamide, TMSOTf=trimethylsilyltrifluoromethaesulfonate, MeCN, 48%.
Scheme 5. Radical nature of the reported fluorination reaction.
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24 h in the dark. After this time, the reaction was diluted with
Conclusion
CH2Cl2 (15 mL) and H2O (15 mL). The layers were separated and the
aqueous layer was extracted twice with CH2Cl2. The combined
organic extracts were washed with brine, dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude residue was
purified by flash chromatography on silica gel.
In summary, cesium oxalates were found to undergo radical
decarboxylative fluorination in the presence of silver nitrate
catalyst and Selectfluor®. The described fluorination transforma-
tion operates under mild conditions and its efficiency for the
preparation of tertiary alkyl fluorides is comparable to the light-
mediated protocols previously reported. Mechanistic studies
confirmed the radical nature of the reaction as well as the dual
role of Selectfluor® as both oxidant and fluorine atom source.
Overall, this simple and practical fluorination protocol contrib-
utes to expand the synthetic tool box for the preparation of
alkyl fluorides.
(4-Fluoro-4-methylpiperidin-1-yl)(phenyl)methanone (3a): Follow-
ing the general procedure GP1 the radical fluorination was carried
out with methyl oxalate 1a (76 mg, 0.25 mmol), acetone (1.25 mL),
an aqueous solution of CsOH (0.26 M, 1.0 mL, 0.26 mmol), Select-
fluor® (177 mg, 0.500 mmol) and AgNO3 (2.1 mg, 0.0125 mmol). The
crude residue was purified by flash chromatography on silica gel
(CH2Cl2/EtOAc: 98/2) to give fluoro-piperidine 3a (40 mg, 73%) as a
white solid. The compound showed satisfactory NMR spectroscopic
data;[8c] 1H NMR (300 MHz, CDCl3) δ 7.47–7.29 (m, 5H, ArH), 4.69–4.30
(br m, 1H, CH2), 3.69–3.45 (br m, 1H, CH2), 3.43–3.03 (br m, 2H, CH2),
3
2.05–1.50 (br m, 4H, 2×CH2), 1.38 (d, 3H, JH-F =21.6 Hz, CH3) ; 19F
NMR (282 MHz, CDCl3) δ À 153.5–À 154.0 (m, 1F).
Experimental Section
3-Fluoro-3-methylheptyl 4-methylbenzenesulfonate (3b): Follow-
ing the general procedure GP1, the radical fluorination was carried
out with methyl oxalate 1b (193 mg, 0.500 mmol), acetone
(2.5 mL), an aqueous solution of CsOH (0.26 M, 2.00 mL,
0.525 mmol), Selectfluor® (354 mg, 1.00 mmol) and AgNO3 (4.3 mg,
0.025 mmol). The crude residue was purified by flash chromatog-
raphy on silica (Pentane/EtOAc: gradient from 95/5 to 90/10) to
give fluoro-tosylate 3b (110 mg, 74%) as a colourless oil;1H NMR
(300 MHz, CDCl3) δ 7.77 (br d, 2H, J=8.4, ArH), 7.33 (br d, 2H, J=8.4,
ArH), 4.19–4.10 (m, 2H, TsOCH2), 2.43 (s, 3H, CH3), 2.10–1.84 (m, 2H,
CH2), 1.61–1.44 (m, 2H, CH2), 1.34–1.17 (m, 4H, 2×CH2), 1.26 (d, 3H,
3JH-F =21.9 Hz, CH3), 0.87 (br t, 3H, J=6.6 Hz CH3); 13C NMR (75 MHz,
CDCl3) δ 145.0 (C), 133.2 (C), 130.1 (2×CH), 128.1 (2×CH), 95.9 (d,
General: All reactions were carried out using dried glassware and
magnetic stirring under an atmosphere of argon. All reagents were
obtained from commercially available sources and used without
further purification. Anhydrous reaction solvents were obtained by
distillation over calcium hydride (dichloromethane, triethylamine)
and over sodium/benzophenone (tetrahydrofuran). Flash column
chromatography was performed on silica gel (40–63 μm or 60–
200 μm) from SdS. Thin-layer chromatography (TLC) were carried
out on pre-coated plates from Merck DC Silica Gel 60 F-254
aluminum sheets and visualized by one or both of the two
following methods: (1) illumination with a short wavelength UV
lamp (λ=254 nm) and/or (2) staining with p-anisaldehyde, phos-
phomolybdic acid or KMnO4 staining solution followed by heating.
3
2
1JC-F =167.3 Hz, C), 66.5 (d, JC-F =6.3 Hz, CH2), 39.9 (d, JC-F =22.4 Hz,
1
Unless otherwise stated, H NMR (300 MHz), 13C NMR (75 MHz), 19F
2
3
CH2), 38.4 (d, JC-F =22.9 Hz, CH2), 25.9 (d, JC-F =5.8 Hz, CH2), 24.6 (d,
2JC-F =24.6 Hz, CH3), 23.1 (CH2), 21.8 (CH3), 14.1 (CH3); 19F NMR
(282 MHz, CD2Cl2) δ À 144.5–À 145.1 (m, 1F); FTIR (νmax cmÀ 1) 2957,
2872, 1598, 1467, 1359, 118, 1174, 1097, 965, 922, 888, 836, 814,
759, 662, 552. HRMS (TOF ESI) m/z calcd for C15H27FNO3S [M+NH4]+
: 320.1696. Found 320.1690.
NMR (282 MHz) spectra were obtained using Bruker Avance 300
spectrometers. Chemical Shifts (δ) are expressed in parts per million
(ppm) and coupling constants (J) in Hertz (Hz). Spin multiplicities
are indicated by the following symbols: s (singlet), d (doublet), t
(triplet), m (multiplet), br (broad signal). 1H-NMR were referenced
to the residual deuterated solvent peak (CDCl3 =7.26 ppm, CD2Cl2 =
5.30 ppm, THF-d8 =3.58 and 1.72 ppm) and 13C-NMR were refer-
enced to the carbon resonance of the solvent (CDCl3 =77.16;
CD2Cl2 =53.84 ppm). Infrared (IR) spectra were recorded on a Perkin
Elmer FT-IR Spectrum 100 spectrometer and the wave number (ν)
of recorded IR-signals are quoted in cm-1. Melting points were
recorded on a Kofler bench device and are uncorrected. Optical
rotations were measured on a Perkin-Elmer polarimeter 341. High
resolution mass spectra were recorded on Water LCT Premier.
1-Azido-3-fluoro-3-methylheptane (3c): Following the general
procedure GP1, the radical fluorination was carried out with methyl
oxalate 1c (129 mg, 0.500 mmol), acetone (2.5 mL), an aqueous
solution of CsOH (0.26 M, 2.00 mL, 0.525 mmol), Selectfluor®
(354 mg, 1.00 mmol) and AgNO3 (4.3 mg, 0.025 mmol). The crude
residue was purified by flash chromatography on silica (Pentane/
EtOAc: 95/5) to give fluoro-azide 3c (60 mg, 69%) as a colourless
1
oil; H NMR (300 MHz, CDCl3) δ 3.39 (t, 2H, J=9.0 Hz, N3CH2), 2.04–
1.77 (m, 2H, N3CH2CH2), 1.69–1.52 (m, 2H, C(F)CH2), 1.45–1.23 (m,
4H, 2×CH2), 1.31 (d, 3H, J=21.9 Hz, C(F)CH3), 0.92 (br t, 3H, J=
Methyl oxalates 1a, 1e, 1h, 1i, 1g, 1m and 1n were prepared
according literature procedure and showed satisfactory NMR
spectroscopic data.[8c] Oxalic acids 1p, 1q, 1r, 1s, 1t and 1u were
prepared according literature procedures and showed satisfactory
NMR spectroscopic data.[8d,g] Experimental details for the prepara-
tion of methyl oxalates 1b, 1c, 1d, 1f, 1j, 1k, 1l, 1o and of oxalic
acids 1’o, 1v are available in the supplementary information.
1
6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 96.4 (d, JC-F =167.2 Hz, C),
3
2
2
47.01 (d, JC-F =6.0 Hz, CH2), 40.0 (d, JC-F =21.7 Hz, CH2), 38.4 (d, JC-
3
2
F =23.2 Hz, CH2), 26.2 (d, JC-F =6.0 Hz, CH2), 24.4 (d, JC-F =24.7 Hz,
CH3), 23.4 (CH2), 14.1 (CH3); 19F NMR (282 MHz, CD2Cl2) δ À 144.9–
À 145.4 (m, 1F); FTIR (νmax cmÀ 1) 2939, 2874, 2092, 1463, 1381, 1262,
1132, 887, 768, 667. HRMS (TOF ESI) m/z calcd for C8H17FN [M+
H(À N2)]+: 146.1345. Found 146.1342.
I. Preparation of alkyl fluorides 3
2-(3-Fluoro-3-methylheptyl)isoindoline-1,3-dione (3d): Following
the general procedure GP1, the radical fluorination was carried out
with methyl oxalate 1d (181 mg, 0.500 mmol), acetone (2.5 mL), an
aqueous solution of CsOH (0.26 M, 2.00 mL, 0.525 mmol), Select-
fluor® (354 mg, 1.00 mmol) and AgNO3 (4.3 mg, 0.025 mmol). The
crude residue was purified by flash chromatography on silica
(Pentane/EtOAc: gradient from 95/5 to 90/10) to give fluoro-
General procedure (GP1) for the synthesis of alkyl fluorides from
°
methyl oxalates: To a 0 C solution of methyl oxalate (1; R=Me)
(0.50 mmol) in acetone (2.50 mL) was added dropwise an aqueous
solution of CsOH (0.525 mmol, 2.00 mL, 0.26 M). The reaction was
stirred for 5–10 min. After this time, the cold bath was removed
and Selectfluor® (1.00 mmol) was added. The reaction mixture was
degassed by sparging with argon for 5 min before adding AgNO3
1
isoindoline 3d (110 mg, 74%) as a colourless oil; H NMR (300 MHz,
CDCl3) δ 7.86–7.78 (m, 2H, ArH), 7.72–7.64 (m, 2H, ArH), 3.85–1.83 (m,
°
(5 mol%). The reaction vessel was sealed and stirred at 25 C for
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2H, NCH2), 2.21–1.82 (m, 2H, NCH2CH2), 1.72–1.57 (m, 2H, C(F)CH2),
3JH-F =22.5 Hz, CH3); 19F NMR (282 MHz, CDCl3) δ À 149.2–À 149.6 (m,
1.39–1.26 (m, 4H, 2×CH2), 1.38 (d, 3H, J=21.6 Hz, C(F)CH3), 0.89 (br
1F).
t, 3H, J=6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 168.4 (2×C), 134.1
4-Fluoro-4-phenyltetrahydro-2H-pyran (3i): Following the general
procedure GP1, the radical fluorination was carried out with methyl
oxalate 1i (132 mg, 0.500 mmol), acetone (4.5 mL), an aqueous
solution of CsOH (0.13 M, 4.00 mL, 0.525 mmol), Selectfluor®
(354 mg, 1.00 mmol) and AgNO3 (4.3 mg, 0.025 mmol). The crude
residue was purified by flash chromatography on silica gel (CH2Cl2/
EtOAc: 98/2) to give fluoro-pyran 3i (61 mg, 67%) as a white solid.
The compound showed satisfactory NMR spectroscopic data;[8c] 1H
NMR (300 MHz, CDCl3) δ 7.42–7.25 (m, 5H, ArH), 4.00–3.79 (m, 4H,
CH2), 2.30–2.00 (m, 2H, CH2), 1.97–1.84 (m, 2H, CH2); 19F NMR
(282 MHz, CDCl3) δ À 160.2–À 160.7 (m, 1F).
1
(2×CH), 132.4 (2×C), 123.4 (2×CH), 96.5 (d, JC-F =167.2 Hz, C), 39.7
3
(d, 2JC-F =22.5 Hz, CH2), 37.6 (d, 2JC-F =23.2 Hz, CH2), 33.6 (d, JC-F
=
3
2
6.0 Hz, CH2), 26.0 (d, JC-F =6.0 Hz, CH2), 24.3 (d, JC-F =24.7 Hz, CH3),
23.2 (CH2), 14.2 (CH3); 19F NMR (282 MHz, CDCl3) δ À 145.8–À 146.3
(m, 1F); FTIR (νmax cmÀ 1) 2956, 2933, 2871, 1772, 1707, 1615, 1467,
1447, 1399, 1372, 1340, 1172, 1148, 1086, 1049, 994, 965, 890, 716,
529. HRMS (TOF API) m/z calcd for C16H20FNO2 [M]À : 277.1478.
Found 277.1483.
4-(3-Fluoro-3-methylbutoxy)benzonitrile (3e): Following the gen-
eral procedure GP1, the radical fluorination was carried out with
methyl oxalate 1e (172 mg, 0.500 mmol), acetone (2.5 mL), an
aqueous solution of CsOH (0.26 M, 2.0 mL, 0.525 mmol), Selectfluor®
(354 mg, 1.00 mmol) and AgNO3 (4.3 mg, 0.025 mmol). The crude
residue was purified by flash chromatography on silica (pentane/
Et2O: gradient from 100/0 to 85/25) to give fluoro-benzenonitrile
3e (94 mg, 90%) as a colourless oil. The compound showed
satisfactory NMR spectroscopic data;[8c] 1H NMR (300 MHz, CD2Cl2) δ
7.59 (d, 2H, J=8.7 Hz, ArH), 6.97 (d, 2H, J=8.7 Hz, ArH), 4.17 (t, 2H,
J=6.6 Hz, OCH2), 2.14 (dt, 2H, 3JH-F =19.5 Hz, J=6.6 Hz, CH2), 1.43 (d,
6H, 3JH-F =21.6 Hz, 2×CH3); 19F NMR (282 MHz, CD2Cl2) δ À 138.1–
À 138.7 (m, 1F).
4-Benzyl-4-fluorotetrahydro-2H-pyran (3j): Following the general
procedure GP1, the radical fluorination was carried out with methyl
oxalate 1j (139 mg, 0.500 mmol), acetone (2.5 mL), an aqueous
solution of CsOH (0.26 M, 2.00 mL, 0.525 mmol), Selectfluor®
(354 mg, 1.00 mmol) and AgNO3 (4.3 mg, 0.025 mmol). The crude
residue was purified by flash chromatography on silica gel
(pentane/Et2O: 97/3) to give fluoro-pyran 3j (33 mg, 34%) as a
1
colourless oil; H NMR (300 MHz, CD2Cl2) δ 7.35–7.17 (m, 5H, ArH),
3.75 (ABX syst., br ddd, 2H, J=11.4, 7.8 and 3.0 Hz, CH2), 3.68–3.57
(br m, 2H, CH2), 2.92 (d, 2H, 3JH-F =22.5 Hz, CH2), 1.86-1.61 (m, 4H, 2×
CH2); 13C NMR (75 MHz, CD2Cl2) δ 136.1 (d, 3JC-F =1.5 Hz, C), 130.9
1
3-Fluoro-3-methylbutyl benzoate (3f): Following the general
procedure GP1, the radical fluorination was carried out with methyl
oxalate 1f (147 mg, 0.500 mmol), acetone (2.5 mL), an aqueous
solution of CsOH (0.26 M, 2.00 mL, 0.525 mmol), Selectfluor®
(354 mg, 1.00 mmol) and AgNO3 (4.3 mg, 0.025 mmol). The crude
residue was purified by flash chromatography on silica (pentane/
Et2O: 95/5) to give fluoro-benzoate 3f (95 mg, 90%) as a colourless
(2×CH), 128.4 (2×CH), 127.0 (CH), 93.2 (d, JC-F =172.5 Hz, C), 63.9
(2×CH2), 47.0 (d, 2JC-F =21.7 Hz, CH2), 35.7 (d, 2JC-F =21.7 Hz, 2×CH2);
19F NMR (282 MHz, CD2Cl2) δ À 159.0–À 160.38 (br m, 1F); FTIR (νmax
cmÀ 1) 2956, 2863, 1496, 1455, 1365, 1227, 1139, 1103, 1013, 840,
720, 699. HRMS (TOF API) m/z calcd for C12H15O [MH-HF]+:
175.1123. Found 175.1112.
4-Fluoro-4-propylcyclohexan-1-one (3k): Following the general
procedure GP1, the radical fluorination was carried out with oxalate
with methyl oxalate 1k (1.10 g, 4.57 mmol), acetone (22.7 mL), an
aqueous solution of CsOH (0.26 M, 18.3 mL, 4.77 mmol), Selectfluor®
(3.22 g, 9.08 mmol) and AgNO3 (39 mg, 0.227 mmol). The crude
residue was purified by flash chromatography on silica (Pentane/
EtOAc gradient from 95/5 to 90/10) to give fluoro-cyclohexanone
1
oil; H NMR (300 MHz, CDCl3) δ 8.08-7.96 (m, 2H, ArH), 7.58–7.50 (m,
3
1H, ArH), 7.48–7.35 (m, 2H, ArH), 4.45 (t, 2H, JH-H =6.9 Hz, BzOCH2),
3
2.10 (dt, 2H, 3JH-F =19.5 Hz, 3JH-H =6.9 Hz, CH2), 1.43 (d, 6H, JH-F
=
21.3 Hz, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 166.7 (C), 133.1 (CH),
1
130.4 (C), 129.7 (2×CH), 128.6 (2×CH), 96.1 (d, JC-F =165.9 Hz, C),
3
2
2
61.1 (d, JC-F =6.0 Hz, CH2), 40.1 (d, JC-F =23.3 Hz, CH2), 27.3 (d, JC-F
=24.7 Hz, 2×CH3); 19F NMR (282 MHz, CDCl3) δ À 137.8–À 138.3 (m,
1F); FTIR (νmax cmÀ 1) 2982, 1716, 1451, 1387, 1374, 1272, 1175, 1151,
1111, 1070, 1026, 708. HRMS (TOF API) m/z calcd for C12H16FO2 [M+
H]+: 211.1134. Found 211.1136.
3k (530 mg, 74%) as a white solid; M. p.=32–33 C; 1H NMR
°
(300 MHz, CDCl3) δ 2.74–2.57 (m, 2H, CH2), 2.31–2.13 (m, 4H, 2×
CH2), 1.93–1.54 (m, 4H, 2×CH2), 1.49–1.36 (m, 2H, CH2), 0.94 (t, J=
7.2 Hz, 3H, CH3); 13C {1H} NMR (75 MHz, CDCl3) δ 211.0 (C), 94.4 (d,
3
5-Fluoro-2,5-dimethylhexan-2-ol (3g): Following the general pro-
cedure GP1, the radical fluorination was carried out with methyl
oxalate 1g (116 mg, 0.500 mmol), acetone (2.5 mL), an aqueous
solution of CsOH (0.26 M, 2.00 mL, 0.525 mmol), Selectfluor®
(354 mg, 1.00 mmol) and AgNO3 (4.3 mg, 0.025 mmol). The crude
residue was purified by flash chromatography on silica (pentane/
Et2O: 60/40) to give fluoro-alcohol 3g (55 mg, 74%) as a colourless
oil. The compound showed satisfactory NMR spectroscopic data;[8c]
1H NMR (300 MHz, CD2Cl2) δ 1.75–1.59 (m, 2H, CH2), 1.57–1.48 (m,
2H, CH2), 1.33 (d, 6H, 3JH-F =21.3 Hz, À C(F)(CH3)2), 1.19 (s, 6H,
À C(OH)(CH3)2); 19F NMR (282 MHz, CD2Cl2) δ À 137.7–À 138.2 (m, 1F).
1JC-F =170.3 Hz, C), 42.0 (d, 2JC-F =22.1 Hz, CH2), 36.8 (d, JC-F
=
=
3
12.0 Hz, 2×CH2), 34.9 (d, 2JC-F =22.9 Hz, 2×CH2), 16.8 (d, JC-F
4.6 Hz, CH2), 14.6 (CH3); 19F NMR (282 MHz, CDCl3) δ À 161.7–À 162.1
(m, 1F); FTIR (νmax cmÀ 1) 2959, 2938, 2916, 2876, 1710, 1430, 1319,
1224, 1212, 1152, 1134, 964, 919, 894, 846, 724, 504. HRMS (TOF CI)
m/z calcd for C9H16FO [M+H]+: 159.1185. Found 159.1183.
(3R,3aS,6S,7R,8aS)-6-Fluoro-3,6,8,8-tetramethyloctahydro-1H-
3a,7-methanoazulene (3l): Following the general procedure GP1,
the radical fluorination was carried out with oxalate 1l (154 mg,
0.500 mmol), acetone (2.5 mL), an aqueous solution of CsOH
(0.26 M, 2.00 mL, 0.525 mmol), Selectfluor® (354 mg, 1.00 mmol)
and AgNO3 (4.3 mg, 0.025 mmol). After work-up, fluoro-methanoa-
zulene 3l was obtained as a crude pale-yellow oil (106 mg, 95%).
The compound was found to be prone to degradation over silica
gel. Therefore, NMR analysis were performed on the crude residue
(diastereoisomer ratio >95:5) and compound 3l showed satisfac-
tory NMR spectroscopic data;[8g] 1H NMR (300 MHz, THF-d8) δ 1.97–
3-(4-Chlorophenyl)-3-fluorobutyl benzoate (3h): Following the
general procedure GP1, the radical fluorination was carried out
with methyl oxalate 1h (196 mg, 0.500 mmol), acetone (2.5 mL), an
aqueous solution of CsOH (0.26 M, 2.00 mL, 0.525 mmol), Select-
fluor® (354 mg, 1.00 mmol) and AgNO3 (4.3 mg, 0.025 mmol). The
crude residue was purified by flash chromatography on silica
(petroleum ether/EtOAc: gradient from 100/0 to 85/15 to give
fluoro-benzoate 3h (120 mg, 78%) as a white solid. The compound
showed satisfactory NMR spectroscopic data;[8c] 1H NMR (300 MHz,
CDCl3) δ 7.87–7.77 (m, 2H, p-Cl-ArH), 7.56–7.47 (m, 1H, À OC(O)ArH),
7.43–7.34 (m, 2H, p-Cl-ArH), 7.29 (br s, 4H, À OC(O)ArH), 4.45–4.22 (m,
1.84 (m, 2H), 1.82–1.65 (m, 5H), 1.64–1.25 (m, 6H), 1.36 (d, 3H, 2JH-F
=
24.3 Hz, CH3), 1.10 (s, 3H, CH3), 1.03 (s, 3H, CH3), 0.87 (d, 3H, J=
7.2 Hz, CH3); 19F NMR (282 MHz, THF-d8) δ À 123.1–À 123.6 (m, 1F).
(5S,8R,9S,10S,13S,14S,17R)-17-Fluoro-10,13,17-trimeth-
ylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one (3m): Fol-
3
2H, OCH2), 2.41 (dt, 2H, JH-F =21.5 Hz, J=7.0 Hz, CH2), 1.71 (d, 3H,
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lowing the general procedure GP1, the radical fluorination was
under reduced pressure. The crude residue was purified by flash
chromatography on silica gel.
carried out with methyl oxalate 1m (195 mg, 0.500 mmol), acetone
(4.5 mL), an aqueous solution of CsOH (0.13 M, 4.00 mL,
0.525 mmol), Selectfluor® (354 mg, 1.00 mmol) and AgNO3 (4.3 mg,
0.025 mmol). The crude residue (diastereoisomer ratio=97:3) was
purified by flash chromatography on silica (petroleum ether/EtOAc:
90/10) to give fluoro-steroid 3m (121 mg, 80%) as a white solid.
The compound showed satisfactory NMR spectroscopic data;[8c] 1H
NMR (300 MHz, CDCl3) δ 2.44–2.15 (m, 3H), 2.13–1.06 (m, 17H), 1.26
((3aR,5R,6S,6aS)-6-Fluoro-2,2,6-trimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl)methyl benzoate (3o): Following the general
procedure GP2 without CsOH, the radical fluorination was carried
out with oxalic acid 1’o (155 mg, 0.408 mmol), acetone (2.1 mL),
H2O (1.7 mL), Selectfluor® (289 mg, 0.816 mmol) and AgNO3
(4.3 mg, 0.025 mmol). The crude residue (diastereoisomer ratio
>99:1) was purified by flash chromatography on silica
(Cyclohexane/EtOAc gradient from 90/10 to 70/30) to give fluoro-
furanose 3o (69 mg, 55%) as a colourless oil. The compound
showed satisfactory NMR spectroscopic data as described previ-
ously.
3
(d, 3H, JH-F =22.0 Hz), 1.05–0.84 (m, 1H), 1.01 (s, 3H), 0.83-0.71 (m,
1H), 0.65 (s, 3H); 19F NMR (282 MHz, CDCl3) δ Major Dia À 142.1–
À 142.6 (m, 1F), Minor Dia À 148.4–À 148.6 (m, 1F).
(8R,9S,10R,13S,14S,17R)-17-Fluoro-10,13,17-trimethyl-
6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]
phenanthren-3-one (3n): Following the general procedure GP1,
the radical fluorination was carried out with methyl oxalate 1n
(193 mg, 0.500 mmol), acetone (2.5 mL), an aqueous solution of
CsOH (0.26 M, 2.00 mL, 0.525 mmol), Selectfluor® (354 mg,
1.00 mmol) and AgNO3 (4.3 mg, 0.025 mmol). The crude residue
(diastereoisomer ratio=97:3) was purified by flash chromatogra-
phy on silica (CH2Cl2/EtOAc gradient from 100/0 to 95/5) to give
fluoro-steroid 3n (122 mg, 80%) as a white solid. The compound
showed satisfactory NMR spectroscopic data;[8c] 1H NMR (300 MHz,
CDCl3) δ 7.04 (d, 1H, J=10.0 Hz, 1H, C(O)CH=CH), 6.21 (dd, 1H, J=
10.0, 2.1 Hz, C(O)CH=CH), 6.05 (br t, 1H, J=1.5 Hz, C(O)CH=C),
2.54–2.28 (m, 2H), 2.04–1.43 (m, 10H), 1.36–0.85 (m, 3H), 1.27 (d, 3H,
3JH-F =22.8 Hz), 1.22 (s, 3H), 0.71 (s, 3H); 19F NMR (282 MHz, CDCl3) δ
Major Dia À 142.2–À 142.8 (m, 1F), Minor Dia À 148.4–À 148.6 (m,
1F).
2-Fluoro-2,3-dihydro-1H-indene (3p): Following the general proce-
dure GP2 the radical fluorination was carried out with oxalic acid
1p (206 mg, 1.00 mmol), acetone (5.0 mL), an aqueous solution of
CsOH (0.26 M, 4.00 mL, 1.05 mmol), Selectfluor® (708 mg,
2.00 mmol) and AgNO3 (34 mg, 0.20 mmol). After 2.5 h, 3,5-bis
(trifluoromethyl)bromobenzene (293 mg, 1.00 mmol) as internal
standard was added to the reaction mixture. 19F NMR analysis of an
aliquot (100 μL) indicated that 3p was obtained in 34% NMR yield.
The compound showed satisfactory NMR spectroscopic data;[8g] 19F
NMR (282 MHz, CDCl3) δ À 173.4–À 174.1 (m, 1F).
(1S,4R)-2-Fluoro-1-isopropyl-4-methylcyclohexane (3q): Following
the general procedure GP2 the radical fluorination was carried out
with oxalic acid 1q (1.14 g, 5.00 mmol), acetone (25.0 mL), an
aqueous solution of CsOH (0.26 M, 20.0 mL, 1.05 mmol), Selectfluor®
(3.54 g, 10.0 mmol) and AgNO3 (170 mg, 1.00 mmol). The crude
residue (3q-1,2-cis:3q-1,2-trans/1.2:1 ratio) was purified by flash
chromatography on silica gel (pentane/EtOAc: gradient from 99/1
to 90/10) to give 3q (184 mg, 23%) as a colourless oil. For analytical
purposes, a fraction (129 mg) of enriched diastereoisomer 3q-1,2-
cis (4.5:1 ratio) and a fraction (55 mg) of enriched diastereoisomer
3q-1,2-trans (1:13 ratio) were isolated during the purification and
characterized separately. The compound 3q-1,2-cis showed satisfac-
tory NMR spectroscopic data;[26] 3q-1,2-cis: 1H NMR (300 MHz,
((3aR,5R,6S,6aS)-6-Fluoro-2,2,6-trimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl)methyl benzoate (3o): Following the general
procedure GP1, the radical fluorination was carried out with methyl
oxalate 1o (1.00 g, 2.54 mmol), acetone (13 mL), an aqueous
solution of CsOH (0.266 M, 10.0 mL, 2.66 mmol), Selectfluor® (1.80 g,
5.07 mmol) and AgNO3 (21 mg, 0.127 mmol). The crude residue
(diastereoisomer ratio >99:1) was purified by flash chromatog-
raphy on silica (Cyclohexane/EtOAc gradient from 90/10 to 70/30)
to give fluoro-furanose 3o (332 mg, 42%) as a colourless oil. The
2
CDCl3) δ 4.88 (br d, 0.18×1H, JH-F =48.9 Hz, CH), 4.30 (dtd, 0.82×
1H, 2JH-F =49.8 Hz, JH-H =10.8, 4.8 Hz, CH), 2.14–1.93 (m, 1.82H), 1.82–
1.53 (m, 2.36H), 1.50–0.75 (m, 13.82H); 19F NMR (282 MHz, CDCl3) δ
Major Dia À 174.9 (dm, J=50.4 Hz, 1F) and Minor Dia À 196.4–
stereochemistry at the newly formed sterocenter was determined
1
by NOESY experiment; [α]20 +7 (c 1.0, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 8.08–8.00 (m, 2H, ArH), 7.60–7.51 (m, 1H, ArH), 7.47–7.38 (m,
1
À 196.9 (m, 1F); 3q-1,2-trans: H NMR (300 MHz, CDCl3) δ 4.88 (br d,
2H, ArH), 5.98 (d, 1H, JH-H =3.6 Hz, CH), 4.63 (AB syst., dd, 1H, J=
3
1H, 2JH-F =48.9 Hz, CH), 2.10–1.93 (m, 1 H, CH2), 1.82–1.53 (m, 4H, 2×
CH, CH2), 1.44–1.25 (m, 1H, CH2), 1.17–0.75 (m, 12H, CH, CH2, 3×
11.7 and 4.5 Hz, CH2), 4.49–4.40 (m, 2H, CH and CH2), 4,27 (ddd, 1H,
3
3JH-F =22.8 Hz, JH-H =6,9 and 4.5 Hz, CH), 1.58 (d, 3H, JH-F =22.5 Hz,
1
CH3); 13C {1H} NMR (75 MHz, CDCl3) δ 90.8 (d, JF-C =168.4 Hz, CH),
CH3), 1.50 (s, 3H, CH3), 1.33 (s, 3H, CH3); 13C {1H} NMR (75 MHz, CDCl3)
δ 166.5 (C), 133.4 (CH), 130.0 (2×CH), 129.9 (C), 128.6 (2×CH), 112.9
2
2
47.4 (d, JF-C =20.1 Hz, CH), 40.4 (d, JF-C =21.1 Hz, CH2), 34.8 (CH2),
29.6 (CH), 26.6 (CH), 24.6 (CH2), 22.4 (CH3), 21.1 (CH3), 20.9 (CH3); 19F
1
2
(C), 105.0 (CH), 101.4 (d, JC-F =177.9 Hz, C), 84.8 (d, JC-F =36.8 Hz,
CH), 84.6 (d, 2JC-F =36.8 Hz, CH), 62.3 (d, 3JC-F =9.1 Hz, CH2), 27.2
(CH3), 26.6 (CH3), 16.3 (d, 2JC-F =22.9 Hz, CH3); 19F NMR (282 MHz,
CDCl3) δ À 170.7–À 171.2 (m, 1F); FTIR (νmax cmÀ 1) 2989, 1720, 1452,
1383, 1316, 1270, 1216, 1080, 1013, 871, 709. HRMS (TOF API) m/z
calcd for C16H20FO5 [M+H]+: 311.1295. Found 311.1293.
NMR (282 MHz, CDCl3) δ À 196.4–À 196.9 (m, 1F); FTIR (νmax cmÀ 1
)
2955, 2927, 2871, 1447, 1370, 1013, 992, 976, 927, 540. HRMS (TOF
ES) m/z calcd for C10H19F [M+H]+: 158.1471. Found 158.1478.
(4-Fluoropiperidin-1-yl)(phenyl)methanone (3r): Following the
general procedure GP2 the radical fluorination was carried out with
oxalic acid 1r (139 mg, 0.50 mmol), acetone (2.50 mL), an aqueous
solution of CsOH (0.26 M, 2.00 mL, 0.26 mmol), Selectfluor®
(354 mg, 1.00 mmol) and AgNO3 (17 mg, 0.10 mmol). The crude
residue was purified by flash chromatography on silica gel (CH2Cl2/
EtOAc: gradient from 100/0 to 98/2) to give fluoro-piperidine 3r
(67 mg, 64%) as a colourless oil. The compound showed satisfac-
tory NMR spectroscopic data;[27] 1H NMR (300 MHz, CDCl3) δ 7.42–
General procedure (GP2) for the synthesis alkyl fluorides from
°
oxalic acids: To a 0 C solution of oxalic acid (1; R=H) (1.00 mmol)
in acetone (5.00 mL) was added dropwise an aqueous solution of
CsOH (1.05 mmol, 4.00 mL, 0.26 M). The reaction was stirred for 5–
10 min. After this time, the cold bath was removed and Selectfluor®
(2.00 mmol) was added. The reaction mixture was degassed by
sparging with argon for 5 min before adding AgNO3 (20 mol%). The
2
7.34 (m, 5H, ArH), 4.87 (br dm, 1H, JH-F =67.0 Hz, CH), 4.29–3.06 (br
°
reaction vessel was sealed and stirred at 25 C for 2–5 h in the dark.
m, 4H, 2×CH2), 2.12–1.52 (br m, 4H, 2×CH2); 19F NMR (282 MHz,
CDCl3) δ À 182.8–À 183.4 (m, 1F).
After this time, the reaction was diluted with CH2Cl2 (30 mL) and
H2O (30 mL). The layers were separated and the aqueous layer was
extracted twice with CH2Cl2. The combined organic extracts were
washed with brine, dried over Na2SO4, filtered and concentrated
3-Fluoro-5α-cholestane (3s): Following the general procedure GP2
the radical fluorination was carried out with oxalic acid 1s (461 mg,
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1.00 mmol), acetone (5.0 mL), an aqueous solution of CsOH (0.26 M,
m, 2H, CH2), 2.40–2.15 (br m, 2H, CH2), 1.74–1.33 (m, 8H, CH2), 1.54
(s, 3H, CH3), 1.15 (br s, 6H, 2×CH3), 1.08 (br s, 6H, 2×CH3); 13C NMR
(75 MHz, CDCl3) [1:1 mixture of rotamers*] δ 170.4 (C), 154.8 (C),
136.0 (C), 129.7 (CH), 128.5 (2×CH), 126.9 (2×CH), 80.4 (C), 60.3 (2×
C), 47.3* (br s, CH2), 39.9 (2×CH2), 38.2* (br s, CH2), 36.4* (br s, CH2),
35.8* (br s, CH2), 31.6 (2×CH3), 24.8 (CH3), 20.5 (2×CH3), 16.9 (CH2);
FTIR (νmax cmÀ 1) 2931, 1767, 1632, 1431, 1378, 1364, 1212, 1173,
1136, 966, 729, 707. HRMS (TOF ESI) m/z calcd for C23H35N2O4 [M+
H]+: 403.2597. Found 403.2590.
4.00 mL, 1.05 mmol), Selectfluor® (708 mg, 2.00 mmol) and AgNO3
(34 mg, 0.20 mmol). The crude residue (3s-3α-F:3s-3β-F/1:2.4
ratio) was purified by flash chromatography on silica gel (pentane)
to give fluoro-steroid 3s (55 mg, 14%) as a colourless solid. For
analytical purposes, a pure fraction (10 mg) of 3s-3α-F and a pure
fraction (27 mg) of 3s-3β-F were isolated and characterized
separately. Both compounds showed satisfactory NMR spectro-
scopic data;[8g] 3s-3α-F:1H NMR (300 MHz, CDCl3) δ 4.78 (dm, 1H,
2JH-F =48.0 Hz, CH), 1.99–1.89 (m, 1H), 1.88–1.74 (m, 2H), 1.69–1.59
(m, 2H), 1.58–1.42 (m, 7H), 1.40–1.18 (m, 9H), 1.17–1.03 (m, 6H),
1.02–0.93 (m, 3H), 0.88 (d, J=6.0 Hz, 3H, CH3), 0.85 (br s, 3H, CH3),
0.83 (br s, 3H, CH3), 0.78–0.66 (m, 1H), 0.76 (br s, 3H, CH3), 0.63 (br s,
3H, CH3); 19F NMR (282 MHz, CDCl3) δ À 180.5–À 181.2 (m, 1F); 3s-
1-Benzoyl-4-methylpiperidin-4-yl (2,2,6,6-tetramethylpiperidin-1-
°
yl) carbonate (3a): To a 0 C solution of methyl oxalate 1a (76 mg,
0.25 mmol) in acetone (1.25 mL) was added dropwise an aqueous
solution of CsOH (0.525 mmol, 1.00 mL, 0.26 M). The reaction was
stirred for 5–10 min. After this time, the cold bath was removed
and NFSI (158 mg, 0.50 mmol) was added. The reaction mixture was
degassed by sparging with argon for 5 min before adding AgNO3
(2.1 mg, 0.0125 mmol) and Na2S2O8 (30 mg, 0.125 mmol). The
2
3
3β-F:1H NMR (300 MHz, CDCl3) δ 4.45 (dtt, 1H, JH-F =49.5 Hz, JH-F
=
10.5 and 5.1 Hz, CH), 2.00–1.84 (m, 2H), 1.83–1.59 (m, 4H), 1.58–1.40
(m, 5H), 1.39–1.17 (m, 10H), 1.15–0.91 (m, 7H), 0.91–0.76 (m, 2H),
0.88 (d, J=6.9 Hz, 3H, CH3), 0.85 (br s, 3H, CH3), 0.83 (br s, 3H, CH3),
0.80 (br s, 3H, CH3), 0.67–0.55 (m, 1H), 0.63 (br s, 3H, CH3); 19F NMR
(282 MHz, CDCl3) δ À 167.5 (dm, 1JF-H =49.5 Hz, 1F).
°
reaction vessel was sealed and stirred at 25 C for 24 h in the dark.
After this time, the reaction was diluted with CH2Cl2 (10 mL) and
H2O (10 mL). The layers were separated and the aqueous layer was
extracted twice with CH2Cl2 (2×10 mL). The combined organic
extracts were washed with brine, dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude residue was
purified by flash chromatography on silica gel (CH2Cl2/EtOAc: 98/2)
to give fluoro-pyran 3a (10 mg, 18%). The compound showed
satisfactory NMR spectroscopic data as described previously.
2-(3-Fluoropropyl)isoindoline-1,3-dione (3t) and 2-propylisoindo-
line-1,3-dione (10): Following the general procedure GP2 the
radical fluorination was carried out with oxalic acid 1t (277 mg,
1.00 mmol), acetone (5.0 mL), an aqueous solution of CsOH (0.26 M,
4.00 mL, 1.05 mmol), Selectfluor® (708 mg, 2.00 mmol) and AgNO3
(34 mg, 0.20 mmol). The crude residue was purified by flash
chromatography on silica gel (pentane/EtOAc: gradient from 90/10
to 50/50) to give fluoro-isoindoline 3t (75 mg, 36%) as a colourless
oil and isoindoline 10 (41 mg, 22%) as colourless oil. Both
compounds showed respectively satisfactory NMR spectroscopic
data;,[8g,28] 3t: 1H NMR (300 MHz, CDCl3) δ 7.87–7.78 (m, 2H, ArH),
7.73–7.64 (m, 2H, ArH), 4.49 (dt, 2H, 2JH-F =47.2 Hz, 2JH-H =5.5 Hz,
III. Synthesis of fluoro-nucleoside 13
(3S,4S,5R)-5-((Benzoyloxy)methyl)-4-fluoro-4-meth-
yltetrahydrofuran-2,3-diyl diacetate (12):
A solution of 3o
(165 mg, 0.532 mmol) in HCO2H (98%, 880 μL) and H2O (120 μL)
2
CH2), 3.82 (t, 2H, J=6.9 Hz, CH2), 2.07 (dm, 2H, JH-F =26.4 Hz, CH2);
°
was heated at 80 C for 12 h. After this time, all volatiles were
2
19F NMR (282 MHz, CDCl3) δ À 220.8 (tt, JF-H =47.2 and 26.4 Hz, 1F).
removed under reduced pressure. The 1,2-diol crude residue was
10: 1H NMR (300 MHz, CDCl3) δ 7.85–7.76 (m, 2H, ArH), 7.73–7.62 (m,
2H, ArH), 3.63 (t, 2H, J=7.2 Hz, CH2), 1.76–1.61 (m, 2H, CH2), 0.92 (t,
3H, J=7.4 Hz, CH3); 13C NMR (75 MHz, CDCl3) δ 168.7 (2×C), 134.0
(2×CH), 132.4 (2×C), 123.3 (2×CH), 39.8 (CH2), 22.1 (CH2), 11.5
(CH3).
dissolved in pyridine (1.0 mL), and Ac2O (590 μL, 5.32 mmol) was
°
added dropwise at 0 C. The reaction mixture was stirred at RT for
°
24 h. After this time, the reaction mixture was quenched at 0 C
with MeOH (100 μL) and then diluted with CH2Cl2 and H2O. The
aqueous layer was extracted with CH2Cl2. The combined organic
layers were successively washed with cold dilute aqueous solution
of HCl (40 mL at 0.1 N and 10 mL at 0.5 N), saturated aqueous
solution of NaHCO3, brine, dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude residue (2:1
mixture of α:β anomers) was purified by flash chromatography on
silica gel (cyclohexane/EtOAc, 7/3) to afford diacetate 12 as a
1-Fluorododecane (3u): (a) Following the general procedure GP2
the radical fluorination was carried out with oxalic acid 1u (258 mg,
1.00 mmol), acetone (5.0 mL), an aqueous solution of CsOH (0.26 M,
4.00 mL, 1.05 mmol), Selectfluor® (708 mg, 2.00 mmol) and AgNO3
(34 mg,
0.20 mmol).
After
2.5 h,
3,5-bis(trifluoromethyl)
bromobenzene (293 mg, 1.00 mmol) as internal standard was
added to the reaction mixture. 19F NMR analysis of an aliquot
(100 μL) indicated that 3u was obtained in 4% NMR yield; (b)
Following the general procedure GP2 without CsOH, the radical
fluorination provided 3u in 18% 19F NMR yield. The compound
showed satisfactory NMR spectroscopic data;[8g] 19F NMR (282 MHz,
CDCl3) δ À 217.7–À 218.2 (m, 1F).
1
colourless oil (139 mg, 74%); H NMR (300 MHz, CDCl3) δ 8.07–7.94
(m, 2H, ArH), 7.81–7.45 (m, 1H, ArH), 7.44–7.34 (m, 2H, ArH), 6.49 (d,
3
0.67×1H, JH-H =3.6 Hz, CH), 6.07 (s, 0.33×1H, CH), 5.32 (dd, 0.67×
1H, J=22.5 and 4.8 Hz, CH), 5.26 (d, 0.33×1H, J=13.2 Hz, CH), 4.72–
4.61 (m, 1H, CH2), 4.52–4.25 (m, 3H, CH and CH2), 2.10 (s, 0.33×3H,
CH3), 2.09 (s, 0.67×3H, CH3), 2.05 (s, 0.33×3H, CH3)„ 2.03 (s, 0.67×
3
3H, CH3), 1.55 (d, 0.67×3H, JH-F =22.8 Hz, CH3), 1.53 (d, 0.33×3H,
3JH-F =22.2 Hz, CH3); 13C {1H} NMR (75 MHz, CDCl3) [*refers to the
minor diastereoisomer when unambiguous distinction is possible] δ
169.7* (C), 169.2 (C), 169.12(C), 169.09 (C), 166.3 (C), 133.4 (CH),
II. Mechanistic Investigation:
1-Benzoyl-4-methylpiperidin-4-yl (2,2,6,6-tetramethylpiperidin-1-
yl) carbonate (9): Following the general procedure GP1, the radical
fluorination was carried out with methyl oxalate 1a (152 mg,
0.50 mmol), acetone (2.5 mL), an aqueous solution of CsOH (0.26 M,
2.00 mL, 0.525 mmol), Selectfluor® (354 mg, 1.00 mmol), AgNO3
(4.3 mg, 0.025 mmol) and TEMPO (80 mg, 0.50 mmol). The crude
residue was purified by flash chromatography on silica
(Cyclohexane/EtOAc gradient from 90/10 to 70/30) to give
carbonate 9 (50 mg, 25%) as a viscous colourless oil; 1H NMR
(300 MHz, CDCl3) [1:1 mixture of rotamers*] δ 7.77 (br s, 5H, ArH),
4.49–4.26* (br m, 1H, CH2), 3.64–3.64* (br m, 1H, CH2), 3.38–3.12 (br
1
1
129.80 (2×CH), 129.7 (C), 99.8 (d, JC-F =182.6 Hz, C), 99.6* (d, JC-F
=
=
3
2
181.2 Hz, C), 99.2* (CH), 93.4 (d, JC-F =5.5 Hz, CH), 84.3* (d, JC-F
20.5 Hz, CH), 82.1 (d, 2JC-F =21.1 Hz, CH), 80.4* (d, 2JC-F =35.5 Hz, CH),
77.5 (overlap with solvent signal and deduced from DEPT experi-
ment, d, 2JC-F =34.7 Hz, CH), 62.9* (d, 3JC-F =12.3 Hz, CH2), 62.2 (d,
3JC-F =12.5 Hz, CH2), 21.1* (CH3), 20.9 (CH3), 20.7* (CH3), 20.4 (CH3),
18.7 (d, JC-F =25.1 Hz, CH3), 17.3* (d, JC-F =24.3 Hz, CH3); 19F NMR
(282 MHz, CDCl3) δ Major dia À 158.2–À 158.6 (m, 1F), Minor dia
À 166.0–À 166.3 (m, 1F); FTIR (νmax cmÀ 1) 2924, 1751, 1721, 1271,
2
2
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Full Papers
doi.org/10.1002/ejoc.202100344
J. Org. Chem. 2013, 9, 2476–2536; c) M. G. Campbell, T. Ritter, Chem. Rev.
2015, 115, 612–633.
1238, 1213, 1080 1070, 1025, 1008. HRMS (TOF ESI) m/z calcd for
C17H19FNaO7 [M+Na]+: 377.1013. Found 377.1007.
[3] a) J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1–PR43; b) T. Liang, C. N.
Neumann, T. Ritter, Angew. Chem. Int. Ed. 2013, 52, 8214–8264; Angew.
Chem. 2013, 125, 8372–8423; c) P. A. Champagne, J. Desroches, J.-D.
Hamel, M. Vandamme, J.-F. Paquin, Chem. Rev. 2015, 115, 9073–9174;
d) X. Yang, T. Wu, R. J. Phipps, F. D. Toste, Chem. Rev. 2015, 115, 826–
870; e) S. Fustero, D. M. Sedgwick, R. Román, P. Barrio, Chem. Commun.
2018, 54, 9706–9725.
[4] a) E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem. 2014, 57, 2832–
2842; b) 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; c) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A.
Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016, 116, 422–518; d) M. Inoue,
Y. Sumii, N. Shibata, ACS Omega 2020, 5, 10633–10640.
[5] For a seminal study, see: M. Rueda-Becerril, C. Chatalova Sazepin, J. C. T.
Leung, T. Okbinoglu, P. Kennepohl, J.-F. Paquin, G. M. Sammis, J. Am.
Chem. Soc. 2012, 134, 4026–4029.
[6] For reviews on radical fluorination transformations, see: a) C. Chatalova-
Sazepin, R. Hemelaere, J.-F. Paquin, G. M. Sammis, Synthesis 2015, 47,
2554–2569; b) B. Lantaño, A. Postigo, Org. Biomol. Chem. 2017, 15,
9954–9973; c) H. Yan, C. Zhu, Science China Chemistry 2017, 60, 214–
222; d) R. Szpera, D. F. J. Moseley, L. B. Smith, A. J. Sterling, V.
Gouverneur, Angew. Chem. Int. Ed. 2019, 58, 14824–14848; Angew.
Chem. 2019, 131, 14966–14991.
[7] X. Li, X. Shi, X. Li, D. Shi, Beilstein J. Org. Chem. 2019, 15, 2213–2270.
[8] For recent contributions on direct radical fluorination involving the
homolytic cleveage of a C(sp3)À Functional group bond, see: a) M. Zhou,
C. Ni, Z. He, J. Hu, Org. Lett. 2016, 18, 3754–3757; b) H. Chen, Z. Liu, Y.
Lv, X. Tan, H. Shen, H.-Z. Yu, C. Li, Angew. Chem. Int. Ed. 2017, 56,
15411–15415; Angew. Chem. 2017, 129, 15613–15617; c) J. Brioche,
Tetrahedron Lett. 2018, 59, 4387–4391; d) J. Y. Su, D. C. Grünenfelder, K.
Takeuchi, S. E. Reisman, Org. Lett. 2018, 20, 4912–4916; e) G. Tarantino,
C. Hammond, ACS Catal. 2018, 8, 10321–10330; f) D. Meyer, H. Jangra, F.
Walther, H. Zipse, P. Renaud, Nature Communication 2018, 9, 4888;
g) F. J. Aguilar Troyano, F. Ballaschk, M. Jaschinski, Y. Özkaya, A. Gómez-
Suárez, Chem. Eur. J. 2019, 25, 14054–14058; h) M. González-Esguevillas,
J. Miró, J. L. Jeffrey, D. W. C. MacMillan, Tetrahedron 2019, 75, 4222–
4227; i) G. H. Lovett, S. Chen, X.-S. Xue, K. N. Houk, D. W. C. MacMillan, J.
Am. Chem. Soc. 2019, 141, 20031–20036; j) Z. Wang, C.-Y. Guo, C. Yang,
J.-P. Chen, J. Am. Chem. Soc. 2019, 141, 5617–5622; k) P. Chen, P. Wang,
Q. Long, H. Ding, G. Cheng, T. Li, M. Li, Org. Lett. 2020, 22, 9325–9330;
l) J. Ma, W. Xu, J. Xie, Science China Chemistry 2020, 63, 187–191; m) W.
Zhang, Y.-C. Gu, J.-H. Lin, J.-C. Xiao, Org. Lett. 2020, 22, 6642–6646.
[9] For recent contributions on remote radical fluorination transformations
involving a HAT, see: a) D. D. Bume, C. R. Pitts, F. Ghorbani, S. A. Harry,
J. N. Capilato, M. A. Siegler, T. Lectka, Chem. Sci. 2017, 8, 6918–6923;
b) C. R. Pitts, D. D. Bume, S. A. Harry, M. A. Siegler, T. Lectka, J. Am.
Chem. Soc. 2017, 139, 2208–2211; c) E. M. Dauncey, S. P. Morcillo, J. J.
Douglas, N. S. Sheikh, D. Leonori, Angew. Chem. Int. Ed. 2018, 57, 744–
748; Angew. Chem. 2018, 130, 752–756; d) H. Guan, S. Sun, Y. Mao, L.
Chen, R. Lu, J. Huang, L. Liu, Angew. Chem. Int. Ed. 2018, 57, 11413–
11417; Angew. Chem. 2018, 130, 11583–11587; e) S. P. Morcillo, E. M.
Dauncey, J. H. Kim, J. J. Douglas, N. S. Sheikh, D. Leonori, Angew. Chem.
Int. Ed. 2018, 57, 12945–12949; Angew. Chem. 2018, 130, 13127–13131;
f) P. Guo, Y. Li, X.-G. Zhang, J.-F. Han, Y. Yu, J. Zhu, K.-Y. Ye, Org. Lett.
2020, 22, 3601–3606; g) A. N. Herron, D. Liu, G. Xia, J.-Q. Yu, J. Am.
Chem. Soc. 2020, 142, 2766–2770.
((2R,3R,4S,5R)-3-Fluoro-4-hydroxy-3-methyl-5-(5-methyl-2,4-di-
oxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl
benzoate (13): To
a RT solution of diacetate 12 (130 mg,
0.37 mmol) in dry MeCN (2.0 mL) were added at RT thymine
(64 mg, 0.51 mmol) and BSA (250 μL, 1.02 mmol). The reaction
°
mixture was heated at 50 C for 5–10 min. After this time, the
homogenous reaction mixture was allowed to cool to RT before
°
being cooled to 0 C. TMSOTf (68 μL, 0.37 mmol) was added and
°
the reaction mixture was heated at 60 C and stirred for 15 h. After
this time, the reaction mixture was cooled to RT and carefully
quenched with a saturated aqueous solution of NaHCO3. The
aqueous layer was extracted with EtOAc (3×15 mL). The combined
organic layers were washed with brine, dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude residue
(diastereoisomer ratio >95:5) was purified by flash chromatog-
raphy on silica gel (CH2Cl2/EtOAc: gradient from 100/0 to 70/30) to
afford fluoro-nucleoside 13 (74 mg, 48%) as a colourless oil. The
stereochemistry at the newly formed sterocenter was determined
1
by NOESY experiment; [α]20 +12 (c 1.0, CH2Cl2); H NMR (300 MHz,
D
CDCl3) [mixture of rotamers*] δ 9.74* and 9.71* (br s, 1H, NHThy),
8.07–7.96 (m, 2H, ArH), 7.58–7.50 (m, 1H, ArH), 7.46–7.35 (m, 2H, ArH),
7.23 (br s, 1H, overlap with solvent signal and deduced from COSY
experiment, CHThy), 6.06 (d, 1H, JH-H =2.7 Hz, CH), 5.25 (dd, 1H, JH-F
3
3
=18.9 Hz and 3JH-H =2.7 Hz, CH), 4.71 (dd, 1H, AB syst., JH-H
=
2
12.3 Hz, 3JH-H =3.9 Hz, CH2), 4.71 (dd, 1H, AB syst., 2JH-H =12.3 Hz,
3JH-H =6.6 Hz, CH2), 4.19 (ddd, 1H, 3JH-F =25.5 and JH-H =6.6 and
3.9 Hz, CH), 2.13 (s, 0.33×3H, CH3), 1.86 (s, 3H, CH3Thy), 1.52 (d, 3H,
3JH-F =22.5 Hz, CH3); 13C {1H} NMR (75 MHz, CDCl3) [mixture of
rotamers*] δ 169.1 (C), 166.3 (C), 163.9 (C), 150.6 (C), 135.0* (CH),
134.9* (CH), 133.6 (CH), 129.8 (2×CH), 129.4 (C), 128.6 (2×CH), 112.1
(C), 100.2 (d, 1JC-F =178.5 Hz, C), 87.9 (CH), 82.2 (d, 2JC-F =20.5 Hz,
2
2
CH), 82.1 (d, JC-F =21.1 Hz, CH), 80.4 (d, JC-F =36.0 Hz, CH), 61.5 (d,
3JC-F =8.5 Hz, CH2), 20.6 (CH3), 16.2 (d, 2JC-F =23.8 Hz, CH3), 12.7 (CH3);
19F NMR (282 MHz, CDCl3) δ À 161.5–À 161.9 (m, 1F); FTIR (νmax cmÀ 1
)
2922, 1691,1263, 1219, 1065, 712, 419. HRMS (TOF ES) m/z calcd for
C20H20FN2O7 [MÀ H]À :419.1255 found 419.1251.
Acknowledgements
Financial support was provided by Normandie Université, CNRS,
INSA Rouen and LABEX SYNORG (ANR-11-LABX-0029). E.V. thanks
the Région Normandie for a doctoral fellowship (RIN-100-2020-
RraFluR).
Conflict of Interest
[10] For recent contributions on remote radical fluorination transformations
involving the homolytic cleveage of a C(sp3)À C(sp3) bond, see: a) J. B.
Roque, Y. Kuroda, L. T. Göttemann, R. Sarpong, Science 2018, 361, 171;
b) X. Zhou, H. Ding, P. Chen, L. Liu, Q. Sun, X. Wang, P. Wang, Z. Lv, M.
Li, Angew. Chem. Int. Ed. 2020, 59, 4138–4144; Angew. Chem. 2020, 132,
4167–4173; c) Y.-C. Lu, H. M. Jordan, J. G. West, Chem. Commun. 2021,
57, 1871–1874 .
The authors declare no conflict of interest.
Keywords: Alkyl fluorides
·
Cesium oxalates
·
Radical
fluorination reactions · Silver catalysis
[11] For recent contributions on direct radical fluorination of a C(sp3)À H
bond, see: a) A. M. Hua, D. N. Mai, R. Martinez, R. D. Baxter, Org. Lett.
2017, 19, 2949–2952; b) D. D. Bume, S. A. Harry, T. Lectka, C. R. Pitts, J.
Org. Chem. 2018, 83, 8803–8814; c) K. E. Danahy, J. C. Cooper, J. F.
Van Humbeck, Angew. Chem. Int. Ed. 2018, 57, 5134–5138; Angew.
Chem. 2018, 130, 5228–5232; d) H. Egami, S. Masuda, Y. Kawato, Y.
Hamashima, Org. Lett. 2018, 20, 1367–1370; e) W. Liu, X. Huang, M. S.
Placzek, S. W. Krska, P. McQuade, J. M. Hooker, J. T. Groves, Chem. Sci.
2018, 9, 1168–1172; f) A. M. Hua, S. L. Bidwell, S. I. Baker, H. P. Hratchian,
R. D. Baxter, ACS Catal. 2019, 9, 3322–3326; g) Y. Takahira, M. Chen, Y.
[1] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2008, 37, 320–330; b) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly,
N. A. Meanwell, J. Med. Chem. 2015, 58, 8315–8359; c) N. A. Meanwell, J.
Med. Chem. 2018, 61, 5822–5880.
[2] a) T. Furuya, J. E. M. N. Klein, T. Ritter, Synthesis 2010, 2010, 1804–1821;
b) G. Landelle, A. Panossian, S. Pazenok, J.-P. Vors, F. R. Leroux, Beilstein
Eur. J. Org. Chem. 2021, 2421–2430
www.eurjoc.org
2429
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Full Papers
doi.org/10.1002/ejoc.202100344
Kawamata, P. Mykhailiuk, H. Nakamura, B. K. Peters, S. H. Reisberg, C. Li,
[15] For selected contributions involving oxalate derivatives as alkyl radical
precursors under light-mediated reductive conditions, see: a) G. L.
Lackner, K. W. Quasdorf, L. E. Overman, J. Am. Chem. Soc. 2013, 135,
15342–15345; b) G. L. Lackner, K. W. Quasdorf, G. Pratsch, L. E. Overman,
J. Org. Chem. 2015, 80, 6012–6024; c) F. W. Friese, A. Studer, Angew.
Chem. Int. Ed. Engl. 2019, 58, 9561–9564; d) G. Ma, C. Chen, S. Talukdar,
X. Zhao, C. Lei, H. Gong, Chem. Commun. 2020, 56, 10219–10222.
[16] For selected contributions involving oxalate derivatives as alkyl radical
precursors under non-light-mediated oxidative conditions, see: a) H.
Togo, M. Aoki, M. Yokoyama, Chem. Lett. 1991, 20, 1691–1694; b) F.
Coppa, F. Fontana, E. Lazzarini, F. Minisci, Chem. Lett. 1992, 21, 1299–
1302; c) F. Coppa, F. Fontana, E. Lazzarini, F. Minisci, G. Pianese, L. Zhao,
Chem. Lett. 1992, 21, 1295–1298.
[17] For selected contributions involving oxalate derivatives as alkyl radical
precursor under non-light-mediated reductive conditions, see:
a) D. H. R. Barton, D. Crich, Tetrahedron Lett. 1985, 26, 757–760; b) S. C.
Dolan, J. MacMillan, J. Chem. Soc. Chem. Commun. 1985, 1588–1589;
c) D. H. R. Barton, D. Crich, J. Chem. Soc. Perkin Trans. 1 1986, 1603–
1611; d) M. Gao, D. Sun, H. Gong, Org. Lett. 2019, 21, 1645–1648; e) Y.
Ye, H. Chen, J. L. Sessler, H. Gong, J. Am. Chem. Soc. 2019, 141, 820–824;
f) H. Chen, Y. Ye, W. Tong, J. Fang, H. Gong, Chem. Commun. 2020, 56,
454–457; g) X. Chen, X. Luo, X. Peng, J. Guo, J. Zai, P. Wang, Chem. Eur.
J. 2020, 26, 3226–3230; h) Y. Ye, H. Chen, K. Yao, H. Gong, Org. Lett.
2020, 22, 2070–2075.
L. Chen, T. Hoshikawa, T. Shibuguchi, P. S. Baran, Synlett 2019, 30, 1178–
1182; h) J. K. Bower, A. D. Cypcar, B. Henriquez, S. C. E. Stieber, S. Zhang,
J. Am. Chem. Soc. 2020, 142, 8514–8521; i) J. N. Capilato, C. R. Pitts, R.
Rowshanpour, T. Dudding, T. Lectka, J. Org. Chem. 2020, 85, 2855–2864.
[12] For recent contributions on radical functionnalization/fluorination
sequences, see: a) C. R. Pitts, B. Ling, J. A. Snyder, A. E. Bragg, T. Lectka,
J. Am. Chem. Soc. 2016, 138, 6598–6609; b) H. Chen, L. Zhu, C. Li, Org.
Chem. Front. 2017, 4, 565–568; c) Y. Li, X. Jiang, C. Zhao, X. Fu, X. Xu, P.
Tang, ACS Catal. 2017, 7, 1606–1609; d) S.-W. Wu, J.-L. Liu, F. Liu, Chem.
Commun. 2017, 53, 12321–12324; e) Q. Zhang, G. Zheng, Q. Zhang, Y. Li,
Q. Zhang, J. Org. Chem. 2017, 82, 8258–8266; f) H. Jiang, A. Studer,
Angew. Chem. Int. Ed. 2018, 57, 10707–10711; Angew. Chem. 2018, 130,
10867–10871; g) Z. Liu, H. Chen, Y. Lv, X. Tan, H. Shen, H.-Z. Yu, C. Li, J.
Am. Chem. Soc. 2018, 140, 6169–6175; h) C.-G. Li, Q. Xie, X.-L. Xu, F.
Wang, B. Huang, Y.-F. Liang, H.-J. Xu, Org. Lett. 2019, 21, 8496–8500;
i) A. S. Pirzer, E.-M. Alvarez, H. Friedrich, M. R. Heinrich, Chem. Eur. J.
2019, 25, 2786–2792; j) P. A. P. Reeve, U. Grabowska, L. S. Oden, D.
Wiktelius, F. Wångsell, R. F. W. Jackson, ACS Omega 2019, 4, 10854–
10865; k) Y. Xie, P.-W. Sun, Y. Li, S. Wang, M. Ye, Z. Li, Angew. Chem. Int.
Ed. 2019, 58, 7097–7101; Angew. Chem. 2019, 131, 7171–7175.
[13] For selected nucleophilic deoxyfluorination reactions, see: a) W. J.
Middleton, J. Org. Chem. 1975, 40, 574–578; b) G. S. Lal, G. P. Pez, R. J.
Pesaresi, F. M. Prozonic, H. Cheng, J. Org. Chem. 1999, 64, 7048–7054;
c) R. P. Singh, J. n. M. Shreeve, Synthesis 2002, 2002, 2561–2578; d) F.
Beaulieu, L.-P. Beauregard, G. Courchesne, M. Couturier, F. LaFlamme, A.
L’Heureux, Org. Lett. 2009, 11, 5050–5053; e) A. L’Heureux, F. Beaulieu,
C. Bennett, D. R. Bill, S. Clayton, F. LaFlamme, M. Mirmehrabi, S.
Tadayon, D. Tovell, M. Couturier, J. Org. Chem. 2010, 75, 3401–3411; f) T.
Umemoto, R. P. Singh, Y. Xu, N. Saito, J. Am. Chem. Soc. 2010, 132,
18199–18205; g) F. Sladojevich, S. I. Arlow, P. Tang, T. Ritter, J. Am.
Chem. Soc. 2013, 135, 2470–2473; h) M. K. Nielsen, C. R. Ugaz, W. Li, A. G.
Doyle, J. Am. Chem. Soc. 2015, 137, 9571–9574; i) L. Li, C. Ni, F. Wang, J.
Hu, Nat. Commun. 2016, 7, 13320; j) T. A. McTeague, T. F. Jamison,
Angew. Chem. Int. Ed. 2016, 55, 15072–15075; Angew. Chem. 2016, 128,
15296–15299; k) J. Guo, C. Kuang, J. Rong, L. Li, C. Ni, J. Hu, Chem. Eur. J.
2019, 25, 7259–7264; l) P. R. Melvin, D. M. Ferguson, S. D. Schimler, D. C.
Bland, M. S. Sanford, Org. Lett. 2019, 21, 1350–1353; m) D. E. Sood, S.
Champion, D. M. Dawson, S. Chabbra, B. E. Bode, A. Sutherland, A. J. B.
Watson, Angew. Chem. Int. Ed. 2020, 59, 8460–8463; Angew. Chem. 2020,
132, 8538–8541; n) S. Zhao, Y. Guo, Z. Su, W. Cao, C. Wu, Q.-Y. Chen,
Org. Lett. 2020, 22, 8634–8637.
[18] N. R. Patel, R. A. Flowers, J. Org. Chem. 2015, 80, 5834–5841.
[19] F. Yin, Z. Wang, Z. Li, C. Li, J. Am. Chem. Soc. 2012, 134, 10401–10404.
[20] Y. Zhu, J. Han, J. Wang, N. Shibata, M. Sodeoka, V. A. Soloshonok, J. A. S.
Coelho, F. D. Toste, Chem. Rev. 2018, 118, 3887–3964.
[21] X. Zhang, Comput. Theor. Chem. 2016, 1082, 11–20.
[22] During the reaction, radical cation 5 may also promote hydrogen atom
abstraction of the substrate/product, thus resulting in the formation of
undesired C-centered radical intermediates. Subsequent participation of
the latter in a FAT step with Selecfluor® could explain the formation of
fluorinated side-products observed in some cases. For a recent example
exploiting the reactivity of radical cation 5 as a HAT reagent in a radical
HAT/FAT sequence, see: F. Ghorbani, S. A. Harry, J. N. Capilato, C. R. Pitts,
J. Joram, G. N. Peters, J. D. Tovar, I. Smajlagic, M. A. Siegler, T. Dudding,
T. Lectka, J. Am. Chem. Soc. 2020, 142, 14710–14724.
[23] A. G. Gilicinski, G. P. Pez, R. G. Syvret, G. S. Lal, J. Fluorine Chem. 1992, 59,
157–162.
[24] a) P. Liu, A. Sharon, C. K. Chu, J. Fluorine Chem. 2008, 129, 743–766;
b) M. Bassetto, M. Slusarczyk, Pharm Pat Anal 2018, 7, 277–299.
[25] H. Vorbrüggen, K. Krolikiewicz, B. Bennua, Chem. Ber. 1981, 114, 1234–
1255.
[14] For selected contributions involving oxalate derivatives as alkyl radical
precursors under light-mediated oxidative conditions, see: a) A. Goosen,
J. Chem. Soc. D 1969, 145a–145a; b) C. C. Nawrat, C. R. Jamison, Y.
Slutskyy, D. W. C. MacMillan, L. E. Overman, J. Am. Chem. Soc. 2015, 137,
11270–11273; c) B. Lipp, A. M. Nauth, T. Opatz, J. Org. Chem. 2016, 81,
6875–6882; d) X. Zhang, D. W. C. MacMillan, J. Am. Chem. Soc. 2016, 138,
13862–13865; e) K. Kiyokawa, T. Watanabe, L. Fra, T. Kojima, S. Minakata,
J. Org. Chem. 2017, 82, 11711–11720; f) V. R. Yatham, Y. Shen, R. Martin,
Angew. Chem. Int. Ed. Engl. 2017, 56, 10915–10919; g) S. Y. Abbas, P.
Zhao, L. E. Overman, Org. Lett. 2018, 20, 868–871; h) L. Guo, F. Song, S.
Zhu, H. Li, L. Chu, Nat. Commun. 2018, 9, 4543; i) X. Y. Zhang, W. Z.
Weng, H. Liang, H. Yang, B. Zhang, Org. Lett. 2018, 20, 4686–4690; j) L.
Guo, H.-Y. Tu, S. Zhu, L. Chu, Org. Lett. 2019, 21, 4771–4776; k) S. P. Pitre,
M. Muuronen, D. A. Fishman, L. E. Overman, ACS Catal. 2019, 9, 3413–
3418; l) H. Li, L. Guo, X. Feng, L. Huo, S. Zhu, L. Chu, Chem. Sci. 2020, 11,
4904–4910.
[26] M. Baumann, I. R. Baxendale, L. J. Martin, S. V. Ley, Tetrahedron 2009, 65,
6611–6625.
[27] Z. Li, Z. Wang, L. Zhu, X. Tan, C. Li, J. Am. Chem. Soc. 2014, 136, 16439–
16443.
[28] H. Konishi, H. Nagase, K. Manabe, Chem. Commun. 2015, 51, 1854–1857.
Manuscript received: March 19, 2021
Revised manuscript received: March 25, 2021
Accepted manuscript online: April 1, 2021
Eur. J. Org. Chem. 2021, 2421–2430
www.eurjoc.org
2430
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