One-pot synthesis of tertiary alkyl fluorides from methyl oxalates by radical deoxyfluorination under photoredox catalysis

Article abstract of DOI:10.1016/j.tetlet.2018.10.063

Tertiary alkyl fluorides have been prepared from methyl oxalates derived from tertiary alcohols by a sequential one-pot hydrolysis/photoredox catalyzed radical deoxyfluorination sequence. The reaction operates under mild conditions and tolerates a wide range of functional groups. This method provides an alternative approach to ionic deoxyfluorination transformations for the incorporation of Carbone–Fluorine quaternary centers into organic molecules.

Full text of DOI:10.1016/j.tetlet.2018.10.063

Accepted Manuscript
One-Pot Synthesis of Tertiary Alkyl Fluorides from Methyl Oxalates by Radical
Deoxyfluorination under Photoredox Catalysis
Julien Brioche
PII:
S0040-4039(18)31294-2
https://doi.org/10.1016/j.tetlet.2018.10.063
TETL 50373
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 September 2018
25 October 2018
27 October 2018
Please cite this article as: Brioche, J., One-Pot Synthesis of Tertiary Alkyl Fluorides from Methyl Oxalates by
Radical Deoxyfluorination under Photoredox Catalysis, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.10.063
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One-Pot Synthesis of Tertiary Alkyl
Fluorides from Methyl Oxalates by Radical
Deoxyfluorination under Photoredox
Catalysis
Leave this area blank for abstract info.
Julien Brioche*
SelectFluor
O
O
MeO
CsO
[Ir] cat.
F
CsOH, H2O
O
O
R3
R2
R3
O
R1
R3
O
R1
Blue LED
R1
25 °C,
R2
R2
tertiary alkyl fluorides

1
Tetrahedron Letters
journal homepage: www.elsevier.com
One-Pot Synthesis of Tertiary Alkyl Fluorides from Methyl Oxalates by Radical
Deoxyfluorination under Photoredox Catalysis
Julien Brioche
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA, 76000 Rouen, France
———
ARTICLE INFO
ABSTRACT
 Corresponding author.
E-mail address: julien.brioche@univ-rouen.fr (J. Brioche)
Article history:
Received
Tertiary alkyl fluorides have been prepared from methyl oxalates derived from tertiary alcohols
by a sequential one-pot hydrolysis/photoredox catalyzed radical deoxyfluorination sequence.
Received in revised form
Accepted
Available online
The reaction operates under mild conditions and tolerates a wide range of functional groups.
This method provides an alternative approach to ionic deoxyfluorination transformations for the
incorporation of Carbone–Fluorine quaternary centers into organic molecules.
2018 Elsevier Ltd. All rights reserved.
Keywords:
Radical Fluorinarion
Photoredox Catalysis
Deoxyfluorinarion
Tertiary Alkyl Fluorides
O
Introduction
OH
HO
O
O
PhO
Organofluorine compounds have found many applications in
industry, especially in agrochemical, pharmaceutical or material
science, due to the unique properties conferred by fluorine
substitution [1]. Notably in medicinal chemistry, the
incorporation of fluorine into a drug candidate can significantly
affect its biological properties compared to its unfluorinated
analogue [2]. The field of fluorine chemistry has thus become of
great interest in organic chemistry, resulting in the development
of a number of fluorination methods that allow the preparation of
aromatic fluorides [3] and, to a lesser extent, of alkyl fluorides
[4]. Consequently, around 20-30% of drugs marketed to date
contain fluorine, mostly in aromatic regions [5]. In the context of
drug design, the development of efficient site selective
fluorination in aliphatic region of complex molecules remains
highly desirable as it would allow to further explore the potential
of biologically active compounds containing alkyl fluorine units.
Among the different alkyl fluoride motifs found in marketed
drugs or pharmaceutical candidates, Carbon–Fluorine quaternary
centers represent only a handful of molecules (Fig. 1), due in part
to the synthetic challenge that represents the construction of such
quaternary centers in organic molecules [6].
O
O
H
N
P
NH
iPrO2C
O
F
H
O
HO
F
O
Sofosbuvir
Fludrocortisone
Figure 1. Drug molecules featuring tertiary alkyl fluoride motifs.
Among the various methods allowing the preparation of alkyl
fluoride derivatives, ionic deoxyfluorination transformation is
one of the most attractive because of the ready availability of the
required alcohol precursors (Fig. 2A). In addition, the
deoxyfluorination reagents PhenoFluor [7] and PyFluor [8]
developed by Riter and Doyle, respectively, have drastically
improved the efficiency of this transformation by limiting the
formation of elimination side products and by improving the
chemoselectivity compared to the frequently used reagent
diethylaminosulfur trifluoride (DAST) [9]. Despite those
improvements, efficient deoxyfluorination reactions is mainly
limited to the preparation of primary and secondary alkyl
fluorides. To further expand the scope and the synthetic
application of the fluorination process, the development of an
efficient deoxyfluorination from tertiary alcohols remains to be
devised.
In this context, radical-based fluorination reactions offer a
great opportunity in reaching this objective. Since the seminal
study of Sammis in 2012 [10], this research area has emerged as
a powerful synthetic approach towards fluorine containing
molecules, especially for the preparation of alkyl fluorinated
derivatives, including many tertiary alkyl fluorides [11]. A
radical fluorination reaction relies on a fluorine atom transfer
(FAT) from a N-F fluorine source [e.g. N-fluoropyridinium salts,

2
Results and Discussion
N-fluorobenzensulfonimide (NFSI) or Selectfluor®] to a C-
centered radical (Fig. 2B). To date, the C-centered radicals
involved in this type of fluorination reactions have been
generated under either thermal or photoinduced methods via
various single electron transfer (SET) processes including radical
decarboxylation (Fig. 2B, a) [12], deborylation (Fig. 2B, b) [13],
halogen-exchange (Fig. 2B, c) [14], addition to alkene (Fig. 2B,
d) [15], direct or remote C(sp3)–H abstraction (Fig. 2B, e) [16],
and C–C bond homolytic cleavage (Fig. 2B, f) [17].
The proposed radical deoxyfluorination was examined in a
preliminary experiment with cesium oxalate 1a, Selecfluor® as a
fluorine source and Ir[dF(CF3)ppy]2(dtbbpy)PF6 as
a
photocatalyst under irradiation with a blue light-emitting diode
(LED) (Scheme 1) [12b]. Under those conditions, the reaction
performed either in MeCN or DMF provided the desired tertiary
alkyl fluoride 2a in 30% and 50% respectively.
F
Me
Me OCOCO2Cs
SelectFluor (3.0 equiv)
A. Ionic deoxyfluorination approach towards alkyl fluorides
photocatalyst (1 mol%)
R2
F
HO
R3
R2
R3
R2
deoxyfluorination
reagent
Blue LED
Solvent, 40 °C,
N
N
R1
R1
R1
Bz
Bz
R3
1a
2a
elimination side product
Scheme 1. Preliminary results: solvent = MeCN (2a, 30% yield);
DMF (2a, 50% yield).
N
N
O
N
Ar
Ar
O
N
S
F
S
3
F
F
From a practical point of view, it occurred to us that the
preparation of cesium oxalate 1a from its precursor methyl
oxalate 3a and the radical deoxyfluorination reaction could be
carried out sequentially in the same pot. With this in mind, we
examined a variety of photocalysts and solvents, the results of
which are summarized in Table 1.
F
PhenolFluorTM
Ar = 2,6(iPr)2C6H3
DAST
PyFluor
B. Radical fluorination approach towards alkyl fluorides
FG
Table 1. Optimization of the reaction condition
F
Me
Me OCOCO2Me
1.
CsOH.H2O (1.05 equiv)
solvent
Fluorine
source
a)
b)
c)
FG = CO2H
FG = B(OR)2
FG = Br or I
F
Activation
N
N
( or h)
2.
SelectFluor (3.0 equiv)
alkyl
radical
Bz
Bz
FAT
photocatalyst (1 mol%)
SET
H
C
3a
2a
Blue LED
T (°C), time,
R
N+ Cl
2 BF4
PhO2S
SO2Ph
d)
e)
f)
T
Time
Yield
(%)a
N
Entry
Catalyst
Solvent
N+
(°C)
(h)
N
F
F
, X
F
Ir[dF(CF3)ppy]2
(dtbbpy)PF6
DMF:H2O
(1:1)
1
2
40
40
40
40
40
40
25
25
25
25
25
16
52
48
Selectfluor
(NFSI)
(NFPy's)
Ir(ppy)2
(dtbbpy)PF6
DMF:H2O
(1:1)
16
16
16
16
16
24
24
24
24
24
C. This work: Radical Deoxyfluorination towards tertiary alkyl fluorides
DMF:H2O
(1:1)
3
Ru(bpz)3(PF6)2
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
none
56
O
Fluorine source
Phtocatalyst
OH
CsO
F
DMF:H2O
(1:1)
O
1.
(COCl)2
4
50
R3
R2
R1
R1
O
R3
R2
R3
R2
visible light
2.
R1
CsOH
THF:H2O
(1.2:1)
5
trace
tertiary
alcohols
1
2
Acetone:H2O
(1.2:1)
R1
via
R3
R2
6
ND (69)b
Acetone:H2O
(1.2:1)
7c
ND (76)b
Figure 2. Deoxyfluorination (A) and radical fluorination (B)
approaches towards alkyl fluorides and working hypothesis (C)
Acetone:H2O
(1.2:1)
8c,d
9c,e
10c
11c,e
0
22
19
0
As part of a research program recently initiated in our
laboratory on the development of new radical fluorination
transformations, we became interested in synthetizing tertiary
alkyl fluorides from abundant and readily available precursors.
Inspired by a joined study of Overman and Macmillan on the
construction of quaternary carbons from cesium oxalates 1
derived from tertiary alcohols under photoredox catalysis [18],
we hypothesized that C-centered radicals generated under similar
conditions could be trapped by a fluorine source to deliver the
corresponding tertiary alkyl fluorides 2 (Fig. 2C). Thanks to
hyperconjugative stabilization of alkyl radicals, such radical
fluorination process should favor the formation of tertiary alkyl
fluorides and avoid the formation of the elimination side product
observed in ionic deoxyfluorination reactions. During the
preparation of this manuscript, Reisman has reported a similar
approach for the synthesis of alkyl chlorides from cesium oxalate
under photoredox catalysis, including four examples of radical
deoxyfluorination which prompt us to disclose our preliminary
results in this communication [19].
Acetone:H2O
(1.2:1)
Acetone:H2O
(1.2:1)
Acetone:H2O
(1:1)
none
a
1
Yield determined by H NMR using 3,5-bis(trifluoromethyl)bromobenzene
b
c
as an internal standard.
d Hydrolysis of 3a not performed. e Reaction carried out in dark.
Isolated yield.
Selecfluor® (2.0 equiv).
As anticipated, the tandem sequential process from methyl
oxalate 3a provided the expected tertiary alkyl fluoride 2a in
yields (52%) similar to the one obtained from 1a (entry 1). A
comparison between the efficacy of Ir(ppy)2(dtbbpy)PF6,
Ru(bpz)3(PF6)2 and fac-Ir(ppy)3 as photocatalysts was then
evaluated (entries 2−4). In all cases, 2a was obtained in a similar
range of yields (48−56%) akin to the one obtained with
Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a catalyst (52%). Among these
catalysts, fac-Ir(ppy)3 was selected to pursue the optimization as
it provided cleaner 19F NMR crude spectra. THF as solvent has a

3
deleterious effect on the reaction (entry 5), whereas alkyl fluoride
2a was isolated in 69% yield when DMF was substituted with
acetone (entry 6). Reducing both the quantity of Selectfluor and
the temperature and increasing the reaction time provided
optimal conditions which led to the isolation of 2a in 76% yield
(entry 7) [20]. It is worth noting that prior hydrolysis of methyl
oxalate 3a into the corresponding cesium oxalate 1a is crucial for
the radical fluorination to occur as no trace of 2a could be
detected by 19F NMR analysis of the crude reaction mixture when
the reaction was carried out with methyl oxalate 3a (entry 8)
[21]. Unexpectedly, control experiments in which light or
photocatalyst was omitted yet again led to the formation of 2a in
22% and 19% yield, respectively (entries 9, 10) [22]. Finally, in
the absence of both light and catalyst, no trace of 2a was
observed (entry 11).
radical position were tested (entries 1 and 2). In both cases, the
desired alkyl fluorides 2b and 2c were isolated in 27% and 22%
yields, alongside a significant amount of the tertiary alcohol
precursors of 3b and 3c (33% and 41% yield, respectively). A
control experiment in which methyl oxalate 3b was only
submitted to hydrolysis in the presence of CsOH provided its
alcohol precursor in 30% yield. This result suggests that
hydrolysis of the alternate ester moiety is a significant competing
side reaction when such type of substrate is used in the
deoxyfluorination protocol. In the case of fully alkyl-substituted
oxalate substrates 3d-3h, the competing side reaction discussed
above was significantly or completely suppressed, allowing the
formation of the desired alkyl fluorides 2d-2h in fair to good
yields (entries 3-7). In addition to demonstrating a good
functional group tolerance (e.g. ester, nitrile, tosylate, alcohol,
ketone, dienone), the radical deoxyfluorination reaction enables
the preparation of fluorinated molecules of biological interest
such as steroids.
The scope of the radical deoxyfluorination was next examined
with various methyl oxalates 3 (Table 2).
Table 2. Scope of the radical deoxyfluorinationa
In summary, this paper described a convenient radical
deoxyfluorination of methyl oxalates derived from readily
available tertiary alcohols. The easy preparation of tertiary alkyl
fluorides under photoredox catalysis at room temperature using
Selecfluor® as a fluorine source complements usefully the
literature methods.
1.
CsOH.H2O (1.05 equiv)
acetone:H2O (1.2:1)
OCOCO2Me
F
2
R3
R2
R3
R2
R1
R1
2.
SelectFluor (2.0 equiv)
fac-Ir(ppy)3 (1 mol%)
3
Blue LED
25 °C, 24 h,
Appendix A. Supplementary Data
Yield
(%)b
Entry
Oxalate
Alkyl fluoride
Supplementary data associated with this article can be found,
in the online version, at
F
OCOCO2Me
1
27
Acknowledgments
O
O
The author wishes to thank Prof. Serge Piettre for critical
reading of the manuscript and for helpful discussions. This work
has been partially supported by Normandie Université, CNRS,
INSA Rouen, and LABEX SYNORG (ANR-11-LABX-0029).
This paper is respectfully dedicated to Prof. Samir Zard (École
Polytechnique, Palaiseau, France).
3b
2b
F
OCOCO2Me
OBz
OBz
N
2
3
22
82
Cl
Cl
3c
2c
OCOCO2Me
F
N
References and notes
O
O
3d
2d
F
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(b) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; Del Pozo, C.;
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2014, 114, 2432–2506;
OCOCO2Me
4
5
48
67
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OTs
3e
OTs
2e
F
OCOCO2Me
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OH
OH
(b) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
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3f
2f
OCOCO2Me
Me
Me
F
Me
Me
Me
H
Me
H
6
72
60
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H
H
H
H
O
O
O
O
H
H
3g
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Me
F
OCOCO2Me
Me
Me
Me
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826–870;
Me
H
Me
H
7
H
H
H
H
3h
2h (d.r. = 97:3)
a Reactions performed on 0.25 mmol scale. b Isolated yield.
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neutral or -poor aromatic substituent at the transient C-centered

4
2832–2842;
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irradiation, see: Li, L.; Mu, X.; Liu, W.; Wang, Y.; Mi, Z.; Li, C. -J. J.
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M. Synthesis 2015, 2554–2569;
(b) Lantaño, B.; Postigo, A. Org. Biomol. Chem. 2017, 15, 9954–9973.
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J. G.; Wolf, M. O.; Sammis, G. M.; Paquin, J.-F. J. Am. Chem. Soc.
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[20] The difference of isolated yields of 2a between entry 6 and 7 (Table 1)
could be accounted for the formation of several minor and
uncharacterized fluorinated side-products observed when the reaction
is carried out at 40 °C.
[21] In this case, methyl oxalate 3a was fully recovered after work-up.
[22] (a) Both exeriments have been carried out twice with consistent results
for each run.
(b) In view of the literature redox potentials of the different chemical
species involved in the reaction (fac-Ir(ppy)3, Selecfluor® and cesium
oxalate 1), the formation of 2a in entry 9 (Table 1) can not reasonably