Mechanochemical electrophilic fluorination of liquid beta-ketoesters

Article abstract of DOI:10.1016/j.tet.2017.11.066

An improved substrate scope for the mechanochemical electrophilic fluorination of dicarbonyls is reported. The applicable substrates have now been broadened to include liquid β-ketoesters. Key to this capability is the inclusion of a grinding auxiliary (NaCl) to improve mass transfer and prevent pasting or gumming of the reaction mixture. Notably, the use of a small amount of acetonitrile is critical to increasing the rate of reaction, ensuring complete consumption of starting materials during the short reaction times as well as improving the selectivity for the monofluorinated product in the mill.

Full text of DOI:10.1016/j.tet.2017.11.066

Accepted Manuscript
Mechanochemical electrophilic fluorination of liquid beta-ketoesters
Joseph L. Howard, Yerbol Sagatov, Duncan L. Browne
PII:
S0040-4020(17)31232-2
10.1016/j.tet.2017.11.066
TET 29146
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 October 2017
Revised Date: 20 November 2017
Accepted Date: 23 November 2017
Please cite this article as: Howard JL, Sagatov Y, Browne DL, Mechanochemical electrophilic
fluorination of liquid beta-ketoesters, Tetrahedron (2017), doi: 10.1016/j.tet.2017.11.066.
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Mechanochemical Electrophilic Fluorination
of Liquid Beta-Ketoesters
Leave this area blank for abstract info.
Joseph L. Howard, Yerbol Sagatov, Duncan L. Browne
School of Chemsitry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK

1
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Tetrahedron
journal homepage: www.elsevier.com
Mechanochemical Electrophilic Fluorination of Liquid Beta-Ketoesters
Joseph L. Howarda, Yerbol Sagatova and Duncan L. Browne a,
aSchool of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An improved substrate scope for the mechanochemical electrophilic fluorination of dicarbonyls
is reported. The applicable substrates have now been broadened to include liquid β-ketoesters.
Key to this capability is the inclusion of a grinding auxiliary (NaCl) to improve mass transfer
and prevent pasting or gumming of the reaction mixture. Notably, the use of a small amount of
acetonitrile is ciritical to increasing the rate of reaction, ensuring complete consumption of
starting materials during the short reaction times as well as improving the selectivity for the
monofluorinated product in the mill.
Available online
Keywords:
Mechanochemistry
Fluorination
2009 Elsevier Ltd. All rights reserved
.
Liquid Assisted Grinding
β-Ketoesters
Ball mill
———
Corresponding author. Tel.: +44 (0)29 2087 5571; e-mail: dlbrowne@cardiff.ac.uk

2
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1. Introduction
mixture. For example, when one or more reagents are liquid, the
reaction mixture can become a gum or paste that does not mix
efficiently and can lead to poor conversions. This can often be
overcome by adding an inert solid as a grinding auxiliary, which
can improve the texture of the reaction mixture and aid mass and
energy transfer.9 Such considerations are particularly important
when considering one-pot, multistep mechanochemical
processes.10
Mechanochemistry is an emerging tool for organic synthesis,
with a variety of synthetically important transformations now
reported as possible under milling conditions in the absence of
solvent.1 From a sustainability perspective, it is highly desirable
to operate under neat conditions, producing little or no solvent
waste for the reaction part of a chemical synthesis process.2
However, mechanochemical milling methods can also
complement traditional solution-based synthetic methods. There
are several examples of reactions that can be performed
mechanochemically in shorter times, with different selectivities
or that yield reaction products different from those afforded by
solution based reaction.3 With regards to scaling up reactions, it
has been demonstrated that mechanochemical processes can be
performed on scales useful for the manufacture of MOFs by
making use of twin-screw extrusion.4 However, the differences in
reactivity observed under mechanochemical conditions are not
well understood and are often not expected or predicted. There
are many parameters involved in mechanochemical processes,
finding optimal conditions can be challenging.5 One such
phenomenon is liquid assisted grinding (LAG), whereby the
addition of a small quantity of liquid can lead to significant
changes in the outcome of a mechanochemical reaction.6 Our
recent work, in which we reported the first mechanochemical
fluorination, is one such example.7 It was found that under LAG
conditions, the selectivity of fluorination was significantly
improved compared to neat reaction conditions. There are also
several examples in which LAG enhances the rate of reaction,
and it has also been demonstrated that both the quantity and
identity of the added liquid can be used to switch between
polymorphic forms.8 A further consideration is in the physical
state of the reagents, where liquid and solids behave differently,
which is not normally an important factor in solution-based
reactions. Under mechanochemical milling, this can have a
significant effect on the performance of the reaction, possibly due
to changes in the mixing or energy transfer through the reaction
Having recently developed the mechanochemical fluorination
of solid 1,3-diketones, we were interested to extend this to the
fluorination of other nucleophilic carbon centers (Scheme 1). The
controlled and selective fluorination of carbon atoms has been
shown to dramatically alter the properties of materials, including
for example, metabolic stability, solubility, bioavailability,
Mixer Mill
Selectfluor (2 equiv.)
O
O
O
O
O
O
Ph
OEt
[7]
Ph
OEt
Ph
OEt
Previous work - mechanochemical fluorination of solid 1,3 diketones
Additive(s), 30 Hz
2 hours
F
F
F
1a
Selectfluor (2 equiv.)
O
O
3a
2a
O
O
O
O
Solid
[a]
and/or
Yield
Ratio (2a:3a)
R
R
Entry
Additive
R
R
R
R
Mixer Mill, 2 hours
2.7:1
Solid
1
2
3
4
5
-
70%
32%
69%
83%
96%
98%
F
F
F
NaCl [b]
15:1
7.6:1
11:1
13:1
1:7
MeCN (0.125 mL)
This work - mechanochemical fluorination of liquid beta-ketoesters
NaCl [b], MeCN (0.125 mL)
NaCl [b], MeCN (0.250 mL)
Selectfluor (2 equiv.)
O
O
6
NaCl [b], Na CO
O 3 O
2
O
O
Solid
and/or
R
OR
[a] Total yield of 2a and 3a determined by F NMR co
Mixer Mill
as an internal standard. [b]
19
R
OR
R
mpared toOtrRifluorotoluene
Liquid
F
F
F
Twice the total mass of reagents.
Scheme 1 Extending the scope of mechanochemical fluorination
Table 1 Optimization of mechanochemical fluorination of liquid
β-ketoesters
structural rigidity and a molecules overall dipole moment.11 In
this work, we report the modification of our reaction conditions
to allow the fluorination of less reactive, liquid substrates, thus
improving the overall scope of the solventless process.12
2. Results and Discussion

3
RBF
O
The previous conditions demonstrated the successful
ACCEPTED MANUSCRIPT
Selectfluor (2 equiv.)
CN
mechanochemical fluorination of solid 1,3-diketones, initial
investigations here focused on the less reactive, liquid
β-ketoesters. These can react with an electrophilic source of
fluorine to afford the monofluorinated product (2a) or the
difluorinated product (3a). On treating ethylbenzoylacetate (1a)
with Selectfluor under the mechanochemical conditions
previously established for solid 1,3-diketones, a total yield of
70% was obtained (Table 1, Entry 1), with a selectivity of 2.7:1.
The addition of sodium chloride as a grinding auxiliary was
investigated (Table 1, entry 2). This had a detrimental effect on
the total yield, although an improvement in selectivity was
observed. The addition of acetonitrile was investigated in order to
test the effect of LAG conditions on the system (Table 1, Entry
3). Intriguingly this improved the selectivity, but had a
detrimental effect on the yield likely because the reaction mixture
in this case was the consistency of a paste, suggesting poor mass
transfer within the reaction system. Pleasingly, the addition of
20 mL MeCN, r.t.
F
F
3 weeks
O
5; 4%
CN
O
Mixer Mill
Selectfluor (2 equiv.)
4
CN
30 Hz, no MeCN
F
F
3 hours
5; 65%
RBF
O
O
O O O
Selectfluor (2 equiv.)
S
S
Na2CO3 (1 equiv.)
20 mL MeCN, r.t.
6 hours
F
O
O O O
S
S
7; 60%
Mixer Mill
Selectfluor (2 equiv.)
6
O O
O
S
S
Na2CO3 (1 equiv.)
30 Hz, no MeCN
2 hours
F
7; 77%
O
O
O
O
O
O
O
O
electrophilic fluorination of β-ketoesters
Scheme 3 Exploration of electrophilic fluorination of further
O
O
O
O
substrates.
F
F
F F
F
F
2a
3a
2a
3a
conventional - stirring in solution
conventional - stirring in solution
Selectfluor (2 equiv.), 20 mL MeCN, r.t.
Selectfluor (2 equiv.), Na2CO3 (1 equiv.), 20 mL MeCN, r.t.
120 hours
120 hours
89%
1 : 3
2a : 3a
88%
20 : 1
2a : 3a
O
O
O
mechanochemical - solid-state grinding
mechanochemical - solid-state grinding
Selectfluor (2 equiv.), Na2CO3 (1 equiv.), NaCl, milled 30 Hz
1a; liquid
a
32%
15:1
67% RSM
2a : 3a
Selectfluor (2 equiv.)
NaCla
95%
13 : 1
2a : 3a
98%
1 : 7
2a : 3a
2 hours
2 hours
milled 30 Hz.
with 0.250 mL MeCN
without MeCN
liquid assisted - greatly decreased reaction time [2 h vs 120 h]
grinding (LAG) - grinding agent/auxiliary used
- greatly decreased reaction time [2 h vs 120 h]
Selectfluor (2 equiv.), 0.250 mL MeCN, NaCl,amilled 30 Hz, 2 h
Selectfluor (2 equiv.), Na2CO3 (1 equiv.), NaCl,amilled 30 Hz, 2h
Selectfluor (2 equiv.), 0 mL MeCN, NaCl,amilled 30 Hz, 2 h
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
F
F
F
F
F
F
F
F
F
2a; 96%, 13 : 1
32%, 15 : 1 (67% RSM)
2b; 81%, 15 : 1
25%, 4 : 1 (59% RSM)
2c; 95%, 16 : 1
18%, >50:1 (62% RSM)
3a; 98%, 1 : 7
3b; 77%, 1 : 50
3c; 67%, 1 : 4 (5% RSM)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
F
F
F
F
F
F
F
F
F
2d; 88%, 7 : 1
2e; 75%, 17 : 1
2f;b 90%, 20 : 1, 56:44 d.r.
3d; 75%, 1 : 50
3e; 83%, 1 : 16
3f; 42%, 1 : 2 (14% RSM)
15%, 4.4 : 1 (73% RSM)
19%, 7 : 1 (63% RSM)
21%, >50 : 1 (74% RSM)
a) NaCl used as a grinding agent/auxiliary/adsorbent for liquid reactants, the amount used is equal to twice that of the total of all other reactants. b) Starting material is a
low melting point solid. RSM = Recovered Starting Material.
acetonitrile and sodium chloride enhanced both the yield and
selectivity (Table 1, entry 4). Increasing the amount of
acetonitrile improved the yield further (Table 1, entry 5). Finally,
in order to secure the difluorinated product, the addition of a
sodium carbonate as base was used with good effect. Notably,
this reaction under solution based conditions requires five days to
go to completion.
difluorinated β-ketoester 3a was obtained, also requiring 120
hours for the reaction to be complete, with 88% yield. This is in
comparison to the 2 hours required to complete this reaction in
the ball mill, a sixty-fold reduction in the reaction time.
Having demonstrated that the fluorination of the liquid
ethylbenzoylacetate 1a was possible under mechanochemical
conditions, the application of this methodology to other
substrates was tested (Scheme 2, bottom left). Of those
β-ketoesters explored, all were successfully fluorinated when
exposed to two hours of grinding in a ball mill in the presence of
Selectfluor, sodium chloride and acetonitrile LAG. The addition
of
Indeed, this observation is more generally applicable. The
relatively poor nucleophilicity of β-ketoesters is exemplified in
the reaction times required in solution for the fluorination to be
complete (Scheme 2, top). Without a base, the monofluorinated
Scheme 2 Top: Comparison of mechanochemical conditions to reaction in solution. Bottom: Substrate scope of mechanochemical β-ketoester
fluorination
the
β-ketoester 2a was obtained in 88% yield after stirring at room
temperature for 120 hours. On the addition of Na2CO3, the
LAG is paramount to the enhanced reaction rate of this reaction.
Each process was repeated in duplicate but leaving out the added

4
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4.2. General procedure for the synthesis of β-ketoesters.
acetonitrile, as can be seen, significant recovery of starting
materials (~50-75%) are evident under these altered conditions.
This reaction rate enhancement is in complete contrast to our
previous observations with solid diketones!7a Good conversion to
the difluorinated products was also achievable across the same
substrate set resulting in good yields by switching the sodium
chloride and acetonitrile LAG for sodium carbonate base. It is
likely that the sodium carbonate in this instance is also having a
grinding auxiliary effect to improve the reaction texture for the
milling process (Scheme 2, bottom right).
Following a modified literature procedure14; an aqueous
sodium hydroxide solution (1 M, 50 mL) was added to
ethylbenzoylacetate (8.7 mL, 50 mmol). This mixture was stirred
overnight at room temperature then transferred to a separating
funnel. It was washed with dichloromethane (3 x 10 mL) and the
aqueous layer acidified to pH 1 by the addition of aqueous HCl
(3 M). The precipitate was collected by suction filtration and
dried under vacuum to yield benzoylacetic acid (6.325 g,
39 mmol, 78%), which was used without further purification. A
solution of this acid (1.640 g, 10 mmol) and the corresponding
alcohol (10 mmol) in acetonitrile (20 mL) was prepared. To this
solution was added a solution of dicyclohexylcarbodiimide
(2.063 g, 10 mmol) and 4-dimethylaminopyridine (0.061 g,
0.5 mmol) in acetonitrile (10 mL) under rapid stirring. This
mixture was stirred overnight at room temperature then directly
dry loaded onto silica and purified by flash column
chromatography eluting with 40-60 petroleum ether and ethyl
acetate to yield the product.
The mechanochemical fluorination of other activated
methylene groups was also investigated (Scheme 3). As with
changing from 1,3-diketones to β-ketoesters, it was found that
significantly different conditions were required to fluorinate these
in the ball mill. For the β-ketonitrile, despite an extensive
screening of reaction times, additives and different LAG agents,
conditions for the selective monofluorination were not found.
This suggests that the monofluorinated β-ketonitrile is more
reactive than the starting material, this difficulty has also been
observed by others.13 However, the difluorination of β-ketonitrile
4 was successfully achieved by neat milling with 2 equivalents of
Selectfluor to yield compound 5 in 65% yield. The comparable
reaction in a solution of acetonitrile was very slow, with only 4%
of 5 detected after stirring at room temperature for 3 weeks.
4.3. isopropyl 3-oxo-3-phenylpropanoate (1b)
1
1.820 g, 8.8 mmol, 88%, 3:1 keto:enol. yellow oil. H NMR
(400 MHz, CDCl3) δ 12.59 (s, enol), 7.86 (t, J = 7.7 Hz, 2H),
7.67 (t, J = 11.0 Hz, enol), 7.57 – 7.44 (m, 1H), 7.43 – 7.28 (m,
2H), 5.55 (s, enol), 5.06 (sep, J = 6.2 Hz, enol), 4.99 (sep, J =
6.3 Hz, 1H), 3.87 (s, 2H), 1.22 (d, J = 6.3 Hz, enol), 1.14 (d, J =
6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 192.7, 167.1, 133.7,
128.8, 128.5, 126.1, 69.1, 46.4, 22.0. IR: 1732, 1684, 1265, 1200,
1103, 689 cm-1. HRMS (ES+) [C12H14O3 + Na] calc. 229.0841,
found 229.0849.
The fluorination of bis-sulfone 6 was also investigated
(Scheme 3), and on being subjected to ball milling with
Selectfluor this substrate produced the monofluorinated product 7
in 77% yield after milling for 2 hours with Selectfluor and
Na2CO3. Increasing the reaction time further led to slow
formation of the difluorinated bis-sulfone. The comparable
monofluorination reaction in solution was slightly slower than
the mechanochemical reaction, leading to a 60% yield after 6
hours.
4.4. pentyl 3-oxo-3-phenylpropanoate (1c)
1
0.760 g, 4.9 mmol, 49%, 2.5:1 keto:enol. yellow oil. H NMR
(400 MHz, CDCl3) δ 12.59 (s, enol), 7.93 (d, J = 7.9 Hz, 2H),
7.77 (d, J = 7.8 Hz, enol), 7.57 (t, J = 7.4 Hz, 1H), 7.52 – 7.35
(m, 2H), 5.66 (s, enol), 4.19 (t, J = 6.7 Hz, enol), 4.13 (t, J = 6.7
Hz, 2H), 3.98 (s, 2H), 1.690 - 1.70 (m, enol), 1.64 – 1.52 (m,
2H), 1.36 (dd, J = 8.5, 5.3 Hz, enol), 1.31 – 1.16 (m, 4H), 0.91 (t,
J = 6.6 Hz, enol), 0.85 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 192.6, 173.4, 171.5, 167.6, 136.1, 133.8, 133.5, 131.3,
128.8, 128.6, 128.6 , 126.1, 87.4, 65.7, 64.6, 46.1, 28.5, 28.2,
28.1, 27.9, 22.4, 22.3, 14.0, 14.0. IR: 1738, 1686, 1450, 1411,
1263, 1190, 1144, 978, 775, 754, 687 cm-1. HRMS (ES+)
[C14H18O3 + Na] calc. 257.1154, found 257.1144
3. Conclusion
The mechanochemical fluorination of liquid β-ketoesters has
been achieved, making use of liquid assisted grinding and a
grinding auxiliary. In this way, good yields of mono- and di-
fluorinated β-ketoesters were obtained with good selectivities.
The conditions were further modified to fluorinate a β-ketonitrile
and bis-sulfone. It is noteworthy that the use of mechanochemical
conditions enabled shorter reaction times to the corresponding
solution based reactions.
4. Experimental section
4.5. benzyl 3-oxo-3-phenylpropanoate15 (1d)
4.1. General
1
2.176 g, 8.6 mmol, 86%, 10:3 keto:enol. yellow oil. H NMR
1H, 19F and 13C NMR spectra were obtained on Bruker 400
UltrashieldTM and Bruker 500 MHz spectrometers with
chloroform-d as deuterated solvent. The obtained chemical shifts
δ are reported in ppm and are referenced to the residual solvent
signal. Spin-spin coupling constants J are given in Hz. High
resolution mass spectral (HRMS) data were obtained on a
Thermo Scientific LTQ Orbitrap XL by the EPSRC UK National
Mass Spectrometry Facility at Swansea University or on a
Waters MALDI-TOF mx in Cardiff University. Infrared spectra
were recorded on a Shimadzu IR-Affinity-1S FTIR spectrometer.
Melting points were measured using a Gallenkamp apparatus and
are reported uncorrected. The ball mill used was a Retsch MM
400 mixer mill. Unless otherwise stated, mechanochemical
reactions were performed in 10 mL stainless steel jars with one
stainless steel ball of mass 4 g. All chemicals were obtained from
commercial sources and used without further purification unless
stated otherwise.
(400 MHz, CDCl3) δ 12.48 (s, enol), 7.90 (d, J = 8.0 Hz, enol),
7.86 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 7.9 Hz, enol), 7.51 (t, J =
7.5 Hz, 1H), 7.44 – 7.24 (m, 7H), 5.68 (s, enol), 5.19 (s, enol),
5.13 (s, 2H), 3.98 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 192.3,
167.4, 135.4, 133.8, 128.8, 128.6, 128.6, 128.5, 128.4 , 128.3,
67.1, 45.9. IR: 1738, 1682, 1263, 1182, 1140, 752, 689 cm-1.
HRMS (ES+) [C16H14O3 + Na] calc. 277.0841, found 277.0842
4.6. cyclohexyl 3-oxo-3-phenylpropanoate (1e)
1
2.135 g, 8.7 mmol, 87%, 2.5:1 keto:enol. yellow oil. H NMR
(400 MHz, CDCl3) δ 12.70 (s, enol), 7.94 (d, J = 7.9 Hz, 2H),
7.77 (d, J = 7.8 Hz, enol), 7.57 (t, J = 7.4 Hz, enol), 7.52 – 7.37
(m, 3H), 5.66 (s, enol), 4.95 – 4.88 (m, enol), 4.88 – 4.79 (m,
1H), 3.97 (s, 2H), 2.09 – 1.10 (m, 10H). 13C NMR (101 MHz,
CDCl3) δ 192.7, 166.9, 133.6, 128.7, 128.5, 126.0, 87.9 , 73.8,
46.4, 31.3, 25.3, 23.5. IR: 2936, 2859, 1732, 1684, 1449, 1263,

5
4.12. benzyl 2-fluoro-3-oxo-3-phenylpropanoate (2d)15
1194, 1013, 756, 689 cm-1. HRMS (ES+) [C15H1 O3 + Na] calc.
269.1154, found 269.1154
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8
0.239 g, 0.88 mmol, 88%, 7:1 mono:di, dark yellow liquid. 1H
NMR (400 MHz, CDCLl3) δ 8.00 (d, J = 7.8 Hz, 2H), 7.63 (t, J
= 7.3 Hz, 1H), 7.47 (t, J = 7.4 Hz, 3H), 7.31 (s, 4H), 5.92 (d, J =
48.7 Hz, 1H), 5.31 – 5.21 (m, 2H). 13C NMR (101 MHz, CDCl3)
δ 189.5 (d, J = 20.2 Hz), 164.9 (d, J = 24.3 Hz), 134.7, 134.5,
129.7 (d, J = 3.4 Hz), 129.1 (d, J = 4.9 Hz), 129.0, 128.8, 128.8,
128.5, 90.1 (d, J = 198.1 Hz), 68.2. 19F NMR (376 MHz, CDCl3)
δ -190.39 (d, J = 48.6 Hz). IR: 1761, 1688, 1597, 1449, 1101,
955, 743, 687, 586 cm-1. HRMS (EI+): [C16H13O3F] calc.
272.0849, found 272.0850
4.7. (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 3-oxo-3-
phenylpropanoate (1f)
1
1.697 g, 5.6 mmol, 56%, 2.5:1 keto:enol. yellow crystals. H
NMR (400 MHz, CDCl3) δ 12.62 (s, enol), 7.85 (t, J = 11.1 Hz,
2H), 7.68 (d, J = 7.5 Hz, enol), 7.47 (t, J = 7.4 Hz, 1H), 7.40 –
7.25 (m, 4H), 5.56 (s, enol), 4.74 (td, J = 10.8, 4.3 Hz, enol),
4.63 (td, J = 10.9, 4.3 Hz, 1H), 3.86 (q, J = 15.4 Hz, 2H), 2.03 –
1.75 (m, 1H), 1.71 – 1.48 (m, 3H), 1.45 – 1.14 (m, 2H), 1.0 - 0.65
(m, 10H), 0.59 (d, J = 6.9 Hz, 2H). 13C NMR (101 MHz, CDCl3)
δ 192.5, 167.1, 133.6, 128.7, 128.5, 126.0, 87.7, 75.5, 74.1, 47.1,
34.1, 31.3, 26.3, 25.9, 23.6, 23.2, 22.0. IR: 2957, 2932, 2866,
1630, 1576, 1406, 1223, 1182, 1080, 810, 772, 689 cm-1. HRMS
(ES+) [C19H26O3 + Na] calc. 325.1780, found 325.1776. mp 40
°C (dichloromethane)
4.13. cyclohexyl 2-fluoro-3-oxo-3-phenylpropanoate (2e)
1
0.199 g, 0.75 mmol, 75%, 17:1 mono:di, yellow liquid. H
NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.8 Hz, 2H), 7.63 (t, J =
7.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 5.85 (d, J = 48.9 Hz, 1H),
4.96 – 4.90 (m, 1H), 1.91 – 1.15 (m, 10H). 13C NMR (101 MHz,
CDCl3) δ 189.8 (d, J = 20.0 Hz), 164.5 (d, J = 24.2 Hz), 134.6,
133.6 (d, J = 1.9 Hz), 129.6 (d, J = 3.3 Hz), 128.9, 90.2 (d, J =
197.1 Hz), 75.6, 31.3, 31.1, 23.2. 19F NMR (376 MHz, CDCl3) δ
-190.44 (d, J = 49.0 Hz). IR: 2936, 2860, 1755, 1690, 1597,
1449, 1236, 1007, 689 cm-1 HRMS (EI+): [C15H17O3F] calc.
264.1162, found 264.1161
4.8. General procedure for monofluorination of β-ketoesters.
To a 10 mL stainless steel milling jar was added the β-
ketoester (1 mmol), selectfluor (0.708 g, 2 mmol), sodium
chloride (twice the total mass of substrate and selectfluor) and
acetonitrile (0.25 mL). The ball was added and the mixture
milled at 30 Hz for 2 hours. The resulting powder was transferred
into a flask, washing the residue with chloroform (about 40 mL).
The insoluble material was removed by gravity filtration. The
solvent was removed under reduced pressure to yield the product.
The selectivity ratio was determined by fluorine NMR. The yield
was determined from the mass of material recovered.
4.14. (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 2-fluoro-3-oxo-
3-phenylpropanoate (2f)
0.288 g, 0.90 mmol, 90%, 20:1 mono:di, isolated as a mixture
of diastereomers. dr 56:44, yellow oil. H NMR (400 MHz,
1
CDCl3) δ 8.01 (t, J = 6.2 Hz, 2H), 7.61 (t, J = 6.8 Hz, 1H), 7.47
(t, J = 7.2 Hz, 2H), 5.83 (m, 1H), 4.94 – 4.55 (m, 1H), 1.87 –
0.36 (m,18H). 19F NMR (376 MHz, CDCl3) δ -189.94 (d, J =
48.8 Hz), -190.52 (d, J = 48.7 Hz). 13C NMR (101 MHz, CDCl3)
δ 189.6 (d, J = 21 Hz), 189.4 (d, J = 20 Hz), 164.5 (d, J = 23 Hz),
164.4 (d, J = 24 Hz), 134.5, 134.4, 133.4, 129.5, 129.47, 129.41,
129.38, 128.78, 90.3 (d, J = 198 Hz), 90.1 (d, J = 198 Hz), 46.7,
40.5, 33.9, 31.4, 25.6, 22.9, 21.9, 20.5, 16.1, 15.5. IR: 2955,
2870, 1755, 1694, 1449, 1238, 1096, 953, 910, 689 cm-1. HRMS
(ES+) [C19H25O3F + Na] calc. 343.1685, found 343.1683
4.9. ethyl 2-fluoro-3-oxo-3-phenylpropanoate (2a)16
0.201 g, 0.96 mmol, 96%, 12.5:1 mono:di, dark red liquid. 1H
NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.8 Hz, 2H), 7.64 (t, J =
7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 5.86 (d, J = 48.9 Hz, 1H),
4.30 (q, J = 6.8 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 189.7 (d, J = 20.2 Hz), 165.1 (d, J = 24.2 Hz),
134.7, 133.5, 129.7 (d, J = 3.4 Hz), 129.0, 90.2 (d, J = 197.7
Hz), 62.7, 14.1. 19F NMR (376 MHz, CDCl3) δ -190.29 (d, J =
48.8 Hz). IR: 2983, 1759, 1693, 1597, 1448, 1371, 1242, 1095,
686 cm-1. HRMS (ASAP+) [C11H11O3F + H] calc. 211.0770,
found 211.0773
4.15. General procedure for difluorination of β-ketoesters
To a 10 mL stainless steel milling jar was added the β-
ketoester (1 mmol), selectfluor (0.708 g, 2 mmol), sodium
carbonate (0.106 g, 1 mmol) and sodium chloride (twice the total
mass of substrate and selectfluor). The ball was added and the
mixture milled at 30 Hz for 2 hours. The resulting powder was
transferred into a flask, washing the residue with chloroform
(about 40 mL). The insoluble material was removed by gravity
filtration. The solvent was removed under reduced pressure to
yield the product. The selectivity ratio was determined by
fluorine NMR. The yield was determined directly from the mass
of material recovered, except for examples obtained impure (3c
4.10. isopropyl 2-fluoro-3-oxo-3-phenylpropanoate (2b)
0.182 g, 0.81 mmol, 81%, 15:1 mono:di, light brown liquid.
1H NMR (400 MHz, ) δ 8.03 (d, J = 7.8 Hz, 2H), 7.64 (t, J = 7.3
Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 5.83 (d, J = 48.9 Hz, 1H), 5.20
– 5.10 (m, 1H), 1.28 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 6.2 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 189.8 (d, J = 20.1 Hz),
164.6 (d, J = 24.1 Hz), 134.6, 129.6 (d, J = 3.3 Hz), 128.9, 128.6
(d, J = 26.3 Hz), 90.3 (d, J = 197.4 Hz), 71.1, 21.7. 19F NMR
(376 MHz, CDCl3) δ -190.28 (d, J = 48.9 Hz). IR: 2984, 1755,
1692, 1597, 1449, 1098, 689 cm-1 HRMS (ASAP+) [C12H13O3F +
H] calc. 225.0927, found 225.0922
1
and 3f), where the ratio 1:2:3 was determined by H and 19F
NMR and used in comparison to the mass of material obtained to
calculate the yield of the desired product.
4.11. pentyl 2-fluoro-3-oxo-3-phenylpropanoate (2c)
4.16. ethyl 2,2-difluoro-3-oxo-3-phenylpropanoate (3a)17
0.239 g, 0.95 mmol, 95%, 16:1 mono:di, pale red oil. 1H NMR
(400 MHz, CDCl3) δ 8.03 (d, J = 7.8 Hz, 2H), 7.63 (t, J = 7.3
Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 5.88 (d, J = 48.8 Hz, 1H), 4.22
(sep, J = 5.1 Hz, 2H), 1.64 – 1.54 (m, 2H), 1.30 – 1.14 (m, 4H),
0.82 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 189.6 (d,
J = 20.0 Hz), 165.0 (d, J = 24.2 Hz), 134.6, 133.5 (d, J = 1.9
Hz), 129.6 (d, J = 3.3 Hz), 128.9, 90.1 (d, J = 197.3 Hz), 66.8,
28.1, 27.8, 22.2, 13.9. 19F NMR (376 MHz, CDCl3) δ -190.61 (d,
J = 48.8 Hz). IR: 1759, 1694, 1597, 1449, 1240, 1099, 959, 880,
689 cm-1.
1
0.227 g, 1 mmol, 100%, 7:1 di:mono, yellow-green liquid. H
NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.9 Hz, 2H), 7.68 (t, J =
7.4 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H),
1.32 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 185.6 (t,
J = 30.3 Hz), 162.0 (t, J = 30.6 Hz), 135.2, 131.2, 130.1 (t, J =
2.7 Hz), 129.1, 109.9 (t, J = 264.6 Hz), 63.9, 14.0. 19F NMR (376
MHz, CDCl3) δ -107.61 (s). IR: 1770, 1697, 1597, 1450, 1371,

6
Tetrahedron
1307, 1255, 1155, 1097, 1001, 921, 684, 582 cm-1. HRMS
4.22. Preparation of 2,2-difluoro-3-oxo-3-phenylpropanenitrile
ACCEPTED MANUSCRIPT
(5)
(ASAP+) [C11H10O3F2 + H] calc. 229.0676, found 229.0680
4.17. isopropyl 2,2-difluoro-3-oxo-3-phenylpropanoate (3b)
To a 10 mL stainless steel milling jar was added a
benzoylacetonitrile (0.145 g, 1 mmol) and Selectfluor (0.708 g,
2 mmol). A stainless steel ball of mass 4.0 g was added and the
mixture milled at 30 Hz for 3 hours. The resulting powder was
transferred into a flask, washing the residue with chloroform
(approximately 40 mL). The insoluble material was removed by
gravity filtration. The solvent was removed under reduced
pressure to give 2,2-difluoro-3-oxo-3-phenylpropanenitrile 5
0.187 g, 0.77 mmol, 77%, >50:1 di:mono, light yellow liquid.
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 2H), 7.67 (t, J
= 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 5.29 – 5.14 (m, 1H), 1.29
(d, J = 6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 185.7 (t, J =
27.5 Hz), 161.5 (t, J = 30.3 Hz), 135.2, 131.3 (t, J = 1.9 Hz),
130.0 (t, J = 2.7 Hz), 129.1, 109.7 (t, J = 264.5 Hz), 72.5, 21.5.
19F NMR (376 MHz, CDCl3) δ -107.93 (s). IR: 2988, 1769, 1599,
1450, 1307, 1260, 1159, 1092, 922, 831, 685, 584 cm-1. HRMS
(EI+): [C12H12O3F2] calc. 242.0755, found 242.0753
1
(0.118 g, 0.65 mmol, 65%, 50:1 di:mono) as a yellow oil. H
NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.8 Hz, 2H), 7.76 (t, J =
7.5 Hz, 1H), 7.58 (t, J = 7.8 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 181.0 (t, J = 27.6 Hz), 136.3, 130.4 (t, J = 2.5 Hz),
129.5, 129.2 (t, J = 2.6 Hz), 110.3 (t, J = 42.4 Hz), 106.1 (t, J =
260.7 Hz). 19F NMR (376 MHz, CDCl3) δ -92.02 (s). IR: 2345,
2261,1701, 1597, 1450, 1292, 1175, 1094, 887, 716 cm-1. HRMS
(ASAP+) [C9H5NF2O + H] calc. 182.0417, found 182.0415.
4.18. pentyl 2,2-difluoro-3-oxo-3-phenylpropanoate (3c)
0.239 g material, (75:20:5 3c:2c:1c) corresponding to 0.182 g
1
3c, 0.67 mmol, 67%. 4:1 di:mono, colourless oil. H NMR (400
MHz, CDCl3) δ 8.07 (d, J = 7.9 Hz, 2H), 7.67 (t, J = 7.4 Hz,
1H), 7.52 (t, J = 7.6 Hz, 2H), 4.34 - 4.19 (m, 2H), 1.73 – 1.52
(m, 2H), 1.45 – 1.12 (m, 4H), 0.85 (t, J = 6.8 Hz, 3H). 19F NMR
(376 MHz, CDCl3) δ -107.62 (s). 13C NMR (101 MHz, CDCl3) δ
185.5 (t, J = 27.5 Hz), 162.0 (t, J = 30.6 Hz), 135.2, 134.6, 130.0
(t, J = 2.7 Hz), 129.1, 109.9 (t, J = 264.4 Hz), 67.9, 28.0, 27.7,
22.2, 13.9. IR: 2957, 2932, 2868, 1632, 1614, 1450, 1406, 1256,
1200, 1080, 959, 810, 773, 725, 689 cm-1. HRMS (ASAP+)
[C13H16O3F2 + H] calc. 271.1146, found 271.1144
4.23. Preparation of α-fluorobis(phenylsulfonyl)methane (7)
To
a 10 mL stainless steel milling jar was added
bis(phenylsulfonyl)methane (0.296 g, 1 mmol), Selectfluor
(0.708 g, 2 mmol) and sodium carbonate (0.106 g, 1 mmol). A
stainless steel ball of mass 4.0 g was added and the mixture
milled at 30 Hz for 2 hours. The resulting powder was transferred
into a flask, washing the residue with chloroform (approximately
40 mL). The insoluble material was removed by gravity
filtration. The solvent was removed under reduced pressure to
give α-fluorobis(phenylsulfonyl)methane 7 (0.267 g, 0.85 mmol,
85%, 9.5:1 mono:di) as a colourless powder. 1H NMR (400 MHz,
CDCl3) δ 8.09 – 7.93 (m, 4H), 7.86 – 7.74 (m, 2H), 7.69 – 7.58
(m, 4H), 5.71 (d, J = 45.8 Hz, 1H). 13C NMR (126 MHz, CDCl3)
δ 135.9, 135.5, 130.3, 129.6, 105.9 (d, J = 266.2 Hz). 19F NMR
(376 MHz, CDCl3) δ -168.21 (d, J = 45.8 Hz). IR: 2365, 1582,
1449, 1356, 1167, 1096, 1076, 791, 681, 550, 517 cm-1. HRMS
(ES+): [C13H11O4F + H] calc. 315.0161, found 315.0172. mp
104-106 °C (chloroform)
4.19. benzyl 2,2-difluoro-3-oxo-3-phenylpropanoate (3d)15
0.218 g, 0.75 mmol, 75%, >50:1 di:mono, light yellow liquid.
1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.9 Hz, 2H), 7.66 (t, J
= 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.36 – 7.28 (m, J = 5.7
Hz, 5H), 5.34 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 185.4 (t, J
= 27.4 Hz), 161.8 (t, J = 30.7 Hz), 135.2, 133.9, 131.1 (t, J = 1.9
Hz), 130.0 (t, J = 2.7 Hz), 129.1, 129.1, 128.8, 128.6, 109.9 (t, J
= 265.1 Hz), 69.2. 19F NMR (376 MHz, CDCl3) δ -107.40 (s, J =
9.2 Hz). IR: 1773, 1697, 1597, 1450, 1304, 1263, 1155, 1099,
920, 793, 745, 685 cm-1. HRMS (EI+): [C16H12O3F2] calc.
290.0755, found 290.0752
4.20. cyclohexyl 2,2-difluoro-3-oxo-3-phenylpropanoate (3e)
Acknowledgments
0.234 g, 0.83 mmol, 83%, 16:1 di:mono, light yellow liquid.
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.9 Hz, 2H), 7.67 (t, J
= 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 5.04 – 4.95 (m, 1H), 1.90
– 1.18 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 185.6 (t, J =
27.4 Hz), 161.4 (t, J = 30.4 Hz), 135.1, 131.3 (t, J = 1.7 Hz),
130.0 (t, J = 2.7 Hz), 129.1, 109.7 (t, J = 264.2 Hz), 77.0, 31.0,
25.2, 23.3. 19F NMR (376 MHz, CDCl3) δ -107.90 (s). IR: 2940,
2862, 1769, 1697, 1597, 1450, 1306, 1258, 1161, 1101, 1003,
930, 826, 685, 407 cm-1. HRMS (EI+): [C15H16O3F2] calc.
282.1068, found 282.1067
D. L. B. thanks Cambridge Reactor Design for a Ph.D. award to
J. L. H., the Bolashak International Scholarship of the President
of the Republic of Kazakhstan for a Scholarship award to Y. S.,
the EPSRC First Grant Scheme for funding (D.L.B.
EP/P002951/1) and the School of Chemistry at Cardiff
University for generous support. We thank the EPSRC UK
National Mass Spectrometry Facility at Swansea University for
mass spectrometry measurements.
4.21. (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 2,2-difluoro-3-
oxo-3-phenylpropanoate (3f)
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1
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