Microwave assisted fluorination: an improved method for side chain fluorination of substituted 1-arylethanones

Article abstract of DOI:10.1016/j.tet.2009.09.070

A two-step, one-pot microwave (MW) assisted fluorination of 1-arylethanones to their corresponding 1-aryl-2-fluoroethanones has been developed. The first step utilises Selectfluor as a fluorinating agent in methanol forming 1-aryl-2-fluoroethanones and their corresponding dimethyl acetals. In the second step, water is added and Selectfluor acts as a Lewis acid in the hydrolytic cleavage of the dimethyl acetals. Compared to the thermal synthesis, the MW assisted method leads to a reduction in reaction time both in the fluorination and for the dimethyl acetal cleavage. Moreover, the one-pot procedure reduces reagent and solvent consumption. The method is best suited for the preparation of 1-aryl-2-fluoroethanones containing substituents that deactivates electrophilic aromatic substitution, however highly electron deficient ketones such as 1-(3,5-dinitrophenyl)ethanone reacts more slowly. Reactions using electron rich aromatic ketones had a low regioselectivity, and also produced fluoroaromatic products.

Full text of DOI:10.1016/j.tet.2009.09.070

Tetrahedron 65 (2009) 9550–9556
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave assisted fluorination: an improved method for side chain fluorination
of substituted 1-arylethanones
,
Thor Håkon Krane Thvedt a, Erik Fuglseth a, Eirik Sundby b, Bård Helge Hoff a
*
a Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway
b Sør-Trøndelag University College, E. C. Dahls Gate 2, 7004 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2009
Received in revised form 31 August 2009
Accepted 17 September 2009
Available online 20 September 2009
A two-step, one-pot microwave (MW) assisted fluorination of 1-arylethanones to their corresponding
1-aryl-2-fluoroethanones has been developed. The first step utilises SelectfluorÔ as a fluorinating agent in
methanol forming 1-aryl-2-fluoroethanones and their corresponding dimethyl acetals. In the second step,
water is added and SelectfluorÔ acts as a Lewis acid in the hydrolytic cleavage of the dimethyl acetals.
Compared to the thermal synthesis, the MW assisted method leads to a reduction in reaction time both in
the fluorination and for the dimethyl acetal cleavage. Moreover, the one-pot procedure reduces reagent and
solvent consumption. The method is best suited for the preparation of 1-aryl-2-fluoroethanones containing
substituents that deactivates electrophilic aromatic substitution, however highly electron deficient ke-
tones such as 1-(3,5-dinitrophenyl)ethanone reacts more slowly. Reactions using electron rich aromatic
ketones had a low regioselectivity, and also produced fluoroaromatic products.
Keywords:
Microwave
Electrophilic fluorination
SelectfluorÔ
1-Chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis-
(tetrafluoroborate)
Ó 2009 Elsevier Ltd. All rights reserved.
a
-Fluoroacetophenone
Dimethyl acetal
1. Introduction
heating for the preparation of a
-fluoroacetophenones.36 A simple
method using only F-TEDA-BF4 in methanol enabled acetophe-
nones to be fluorinated in decent yields. The method consists of
Microwave irradiation (MW) is a powerful and easily control-
lable heating source. For a number of reactions, especially those
involving polar transition states, significant rate acceleration can be
achieved compared to conventional heating.1–4
two steps; fluorination yielding the target
a-fluoroketone, 3, its
dimethyl acetal, 2, and subsequent hydrolysis to convert 2 into 3,
Scheme 1.
The use of microwaves has also been applied in various forms of
fluorination.5–13 SelectfluorÔ (F-TEDA-BF4) is a relatively stable
electrophilic fluorinating agent,14 and microwave assisted reactions
on 1,3-dicarbonyl compounds,13 aromatic compounds,5 and 1-aryl-
1-nitromethanes,11 have been reported. Moreover, F-TEDA-BF4 has
also been applied as a Lewis acid in MW assisted synthesis.15
H+
O
O
F-TEDA-BF
MeO
OMe
F
4
F
H O
2
MEOH
D
R
R
R
1
2
3
Scheme 1. Fluorination of acetophenones using F-TEDA-BF4 in methanol.
a-Fluoroacetophenones can be synthesised by nucleophilic
displacement,16–21 electrophilic fluorination of ketones, imines or
enamines,22–30 Friedel/Crafts acylation,31,32 coupling chemistry,33
and reaction via diazo ketones.34,35 However, some of these
methods have drawbacks due to the use of hazardous and toxic
chemicals or the involvement of unstable intermediate compounds.
We have recently compared three methods using conventional
Although being very simple, an obvious drawback of the ther-
mal method was the prolonged reaction times, especially for sub-
strates containing electron withdrawing substituents. Moreover,
several of the dimethyl acetals, 2, required heating to reflux in the
presence of trifluoroacetic acid for several hours for complete
conversion to 3.
To improve the usefulness of the method, we have investigated
the use of microwaves to increase the reaction rates and yields in
conversion of 1-arylethanones, 1 to the corresponding 1-aryl-2-
fluoroethanones, 3.
* Corresponding author. Tel.: þ47 73593973; fax: þ47 73550877.
E-mail address: bhoff@chem.ntnu.no (B.H. Hoff).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.070

T.H. Krane Thvedt et al. / Tetrahedron 65 (2009) 9550–9556
9551
2. Results and discussion
The degree of conversion was highly dependant on the solvent
used. No fluorination was observed in t-BuOH or i-PrOH, while
reactions in water and ethanol gave 8 and 12% conversion re-
spectively. The reaction in acetonitrile gave a 36% conversion,
whereas 97% was obtained using methanol as reaction solvent. In
2.1. MW assisted fluorination: solvent, effect (W) and
reaction time
The reaction rate in the thermal fluorination of acetophenones
using F-TEDA-BF4 in MeOH was very dependant on the electronic
properties of the substituents.36 Therefore, initial experiments
using MW as a heating source were performed using 1-(4-bromo-
phenyl)ethanone (1e), which was intermediate with respect to
electronic character. An Anton Paar 3000 microwave instrument
equipped with a magnetic stirrer device was used. The reactions
were performed in sealed Teflon tubes.
addition to the a-fluoroketone, 3e, and its dimethyl acetal, 2e, the
difluoro-compounds 4e and 5e were observed. Although, aliphatic
difluorination appeared in methanol, the reaction proceeded much
faster than in any of the other solvents tested. One could speculate
that methanol shifts the keto/enol equilibrium more to the enol
side and that this is the reason for the solvent dependant rate
acceleration.
Further experiments were undertaken to study how the effect
and reaction time influenced the degree of conversion and product
distribution using 1e as substrate. The effect was varied between 60
and 100 W, and the reaction time was varied between 60 and
100 min. The results are summarised in Table 2.
Running the reaction at 120 W using two equivalents of F-TEDA-
BF4 in methanol revealed that fluorination took place. However,
several other fluorinated compounds and undefined substances
were present in the discoloured reaction mixture. 1H NMR spec-
troscopy was used for the identification of reaction components. The
1H NMR chemical shifts of 1–3e (Scheme 2) were known from
Table 2
a
previous study.36 The presence of 1-(4-bromophenyl)-2,2-
Conversion (conv.) and product distribution after fluorination of 1e in MeOH varying
difluoroethanone (4e) could be confirmed by the characteristic
triplet at 6.24 ppm (JHF¼53.5 Hz). In addition, a triplet with com-
parable coupling constant was observed at 5.82 ppm (JHF¼55.3 Hz).
Analysis after hydrolytic treatment revealed that this substance was
converted to 4e, and was therefore assigned as the dimethyl acetal,
5e. Trace amounts of 1-(4-bromophenyl)-2-chloroethanone (6e),37
was also observed. It is currently unclear if formation of 6e is due to
impurities in F-TEDA-BF4 or decomposition reactions leading to
electrophilic chlorine sources. A chlorinated by-product has pre-
viously been reported in fluorination of thiazole using F-TEDA-BF4.38
MW effect (W) and reaction time
Entry
Effect (W)
Time (min)
Conv.a (%)
3eþ2e (%)
4eþ5e (%)
0
3
11
7
1
2
3
4
5
60
60
80
100
100
60
100
80
60
100
65
91
>99
97
64
87
87
89
85
98
14
a
Conversion was measured by 1H NMR spectroscopy.
The degree of conversion measured by amount of residual 1-(4-
bromophenyl)ethanone (1e) versus fluorinated products depended
on both effect (W) and reaction time. Full conversion was not
obtained at 60 W (Entries 1 and 2), due to insufficient reaction time.
The incomplete conversion at 100 W was probably due to a thermal
decomposition of F-TEDA-BF4 as it was noted that the reaction
mixture turned black. At 80 W, full conversion was obtained
without discolouration of the reaction mixture. As full conversion
and the absence of coloured by-products allowed for easier product
purification, 80 W was selected as the preferred irradiation effect in
the fluorinations.
F-TEDA-BF4
O
O
O
F
F
MeOH
MW
F
Br
Br
Br
1e
3e
4e
O
MeO OMe
MeO OMe
F
Cl
To maximise the yield of the
a-fluoroketone 3e, its dimethyl
F
F
Br
Br
Br
acetal, 2e needed to be hydrolysed. F-TEDA-BF4 has previously
been used as a Lewis acid.15 We therefore tested if cleavage of the
dimethyl acetal 2e could be performed by simply adding water to
the crude reaction mixture followed by MW irradiation. This
proved to be the case, and 2e was readily cleaved by addition of
water and irradiating the reaction mixture at 80 W for 20 min.
This enabled the preparation of 3e using a one-pot two-step
procedure.
6e
2e
5e
Scheme 2. Reaction products after fluorination of 1e in methanol using F-TEDA-BF4.
Follow-up experiments revealed a positive effect both on con-
version and colourof the reaction mixturewhen the effect was in the
range of 80–100 W. Having found a suitable effect (W), the choice of
reaction medium was reevaluated. If possible, it would be beneficial
to avoid the formation of the intermediate dimethyl acetal, 2e.
Moreover, a change in solvent might affect conversion rates due to
temperature effects. The fluorination was performed in six different
solvents and reacted for 60 min at 80 W. The degree of conversion
and product distribution after fluorination are given in Table 1.
2.2. Scope and limitations: substrate structure
To investigate the scope and limitations of the method with
respect to substrate structure, a series of 1-arylethanones, 1a–l,
were fluorinated, see Scheme 3.
Table 1
The conversion (conv.) and product distribution after fluorination of 1e in different
Both substrates with electron donating and withdrawing sub-
stituents were investigated. Compound 1k was included in the
study to investigate if one fluorine atom was sufficient to reduce
ring fluorination as compared to 1a. Compound 1l was used to
investigate the effects of two strong electron withdrawing groups
on the fluorination and the hydrolysis steps. Both steps were per-
formed at 80 W, and the reaction time was varied to obtain high
conversions. Table 3 summarises the conversions and product
distributions after fluorination, the conversions obtained in the
hydrolytic step, and the yields for 3a–l. The optimised reaction
solvents at 80 W for 60 min
Solvent
Conv.a (%) 1e (%) 2e (%) 3e (%) 4e (%) 5e (%) 6e (%)
Acetonitrile 36
64
100
100
88
3
92
NA
d
34
0
0
11
54
6
0
0
0
0
11
d
0
d
2
0
0
1
1
2
t-BuOH
i-PrOH
EtOH
MeOH
Water
0
0
12
97
8
d
b
d
a
30
NA
5
d
a
Conversion was measured by 1H NMR spectroscopy.
b
Ethyl acetals were not observed by 1H NMR spectroscopy.

9552
T.H. Krane Thvedt et al. / Tetrahedron 65 (2009) 9550–9556
O
O
O
MeO OMe
MeO OMe
F
F
Cl
F
1. F-TEDA-BF4 /MeOH,
80 W
Ar
Ar
Ar
Ar
Ar
O
O
F
F
F
F
Ar
Ar
3k, 3m-n
5a-n
2a-n
4a-n
6a-l
2. H2O, 80 W
1a-l
3a-l
Ar:
F
Ar:
BnO
MeO
F
m
F
n
O2N
MeO
R
F
k
NO2
NO2
Figure 1. By-products and intermediates observed in preparation of 3a–l. For structure
elements a–l see Scheme 3.
i
j
a-h
l
R= a (OMe), b (OBn), c (H), d (F), e (Br), f (CF3),
g (CN), h (NO2)
suggested that ring fluorination had taken place. These three sub-
strates exemplify limitations of the method in general. Due to the
complexity of the reaction mixtures, purifications were not
attempted.
In terms of susceptibility towards aromatic fluorination, 1-(3-
fluoro-4-methoxyphenyl)ethanone (1k), (Entry 4), represents
a borderline case. As compared to fluorination of 1a, the extra m-
fluorine in 1k suppressed ring fluorination, and only 5% of 3n and
4n was observed. Aliphatic difluorination leading to compound 4k
and 5k (19%) was however still significant, reducing the isolated
yield to 59%.
Scheme 3. Fluorination of 1a–l using F-TEDA-BF4.
times at 80 W for the two steps are given in Table 4 and the
structures of the by-products are shown in Figure 1.
The MW assisted fluorination of the electron rich 1-aryletha-
nones 1a–b (Table 3, Entries 1–2) gave low yields of the target
products 3a–b. This was due to the formation of additional ring
fluorinated by-products, 3k and 3m, high amounts of a,a-difluor-
oketones, 4a–b and their corresponding dimethyl acetals, 5a–b.
Especially difficult was fluorination of 1-acetonaphthone (1j)
Fluorination of 1c and 1d and subsequent hydrolysis gave 65
and 74% isolated yield of 3c and 3d respectively. In the case of 1c,
unidentified by-products were detected, explaining the lower yield.
(Entry 3), which led to at least three different
a-fluoroketones, their
corresponding dimethyl acetals and
a,a
-difluorides. 1H and 19F
NMR spectroscopic analysis of the crude product mixture
Table 3
MW assisted fluorination and hydrolysis using F-TEDA-BF4: conversion (conv.) and product distribution after fluorination, conversion after hydrolysis and yields of 3a–l.
Isolated yields are reported unless otherwise stated. For reaction times see Table 4
Entry
Substrate
Fluorination
Conv.a (%)
Hydrolysis
Conv. (%)
2 (%)
3 (%)
4þ5 (%)
Others (%)
Yield (%)
Product
1
2
3
4
5
6
7
8
p-MeO (1a)
p-BnO (1b)
1-Naphthyl (1j)
m-F, p-OMe (1k)
H (1c)
p-F (1d)
p-Br (1e)
p-CF3 (1f)
p-CN (1g)
>99
>99
90
>99
>99
>99
>99
>99
99
11
12
6
44
46
40
53
61
67
63
52
62
24
36
3
18
18
nd
19
12
9
11
6
6
27 (2kþ3k)
24 (2mþ3m)
Multiplec
5 (2nþ3n)
1 (6c)
1 (6d)
1 (6e)
1 (6f)
1 (6g)
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
97
46b
46b
38b
59
65
74
81
69
86
82
72
41
3a
3b
3j
3k
3c
3d
3e
3f
23
26
23
24
41
30
70
58
88
9
3g
3h
3i
10
11
12
p-NO2 (1h)
m-NO2 (1i)
3,5-di-NO2 (1l)
>99
98
94
5
4
3
<1 (6h)
1 (6i)
3 (7l)
3l
a
Conversion was measured by 1H NMR spectroscopy.
Reaction yield of
Not identified.
b
c
a
-fluoroketone as quantified by 1H NMR spectroscopy using 1-(4-methoxyphenyl)ethanone as standard.
Table 4
Comparison of the MW (80 W) and thermal process for the preparation of 3a–l (reaction time and yield)
Entry
Substrate
MW
Thermal
Rx. time
Rx. time
Rx. time
Yield (%)
Rx. time
Yield (%)
fluorination (min)
hydrolysis (min)
fluorination (h)
hydrolysis (h)
1
2
3
4
5
6
7
8
p-MeO (1a)
p-BnO (1b)
1-Naphthyl (1j)
m-F, p-OMe (1k)
H (1c)
p-F (1d)
p-Br (1e)
p-CF3 (1f)
p-CN (1g)
60
60
60
60
60
60
80
85
80
50
60
120
15
15
15
15
15
20
15
25
30
30
30
30
46a
46a
38a
59
65
74
81
69
86
82
72
41
48
72
144
96
96
96
125
144
192
261
336
500c
1 (rt)
1 (rt)
1 (rt)
3.5 (rt)
3.5 (rt)
3.5 (rt)
24 (rt)
20 (reflux)
20 (reflux)
20 (reflux)
20 (reflux)
336d (reflux)
67b
58b
50a
67
66b
25b
77b
73b
64b
70b
73
9
10
11
12
p-NO2 (1h)
m-NO2 (1i)
3,5-di-NO2 (1l)
39
a
Reaction yield quantified by 1H NMR spectroscopy using 1-(4-methoxyphenyl)ethanone as standard.
b
c
Results from previous study.36
82% conv.
d
63% conv.

T.H. Krane Thvedt et al. / Tetrahedron 65 (2009) 9550–9556
9553
In the fluorination of 1d–i (Entries 5–11), aromatic fluorination
was not observed. Moreover, moving down Table 3, as the elec-
tronic withdrawing character of the substituents increases, the
Compared to the thermal process, higher or comparable yields
were obtained in the MW assisted fluorination and hydrolysis
starting with 1c–i. The largest difference in yield when comparing
the two methods is seen in preparation of 3d and 3g.
level of the
a,a-difluorides, 4 and 5 observed was also reduced.
Higher yields were experienced, and the products could be
obtained in 69–86% isolated yield. Electron withdrawing groups on
the aromatic ring increased both the amounts and the stability of
the dimethyl acetals. As a consequence, the reaction time in the
hydrolytic step had to be increased from 15 to 30 min.
Another limitation to the presented method is exemplified by
fluorination of 3,5-dinitroacetophenone (1l), (Entry 12). This sub-
strate required prolonged reaction time, however, a 94% conversion
was obtained by applying 80 W for 2 h.
The dimethyl acetal 2d was previously found to be highly vol-
atile, and this limited the isolated yield of the reported thermal
reaction.36 The volatility is not a problem in the MW process, as the
isolation of 2d is not required. The lower yield of 3g in the thermal
process is probably due to side reactions at the cyano-group, taking
place during the prolonged reaction time.
The MW assisted fluorination of 1l was hampered by a low
reaction rate, and a,a-difluoride formation during hydrolysis. This
gave 41% of 3l. By comparison, the thermal process from 1l also
gave a moderate 39% isolated yield after a total of 5 weeks reaction
time.
The reaction rate in the thermal fluorination was correlated with
the electronic properties of the substituents. For the MW assisted
fluorination, an increase in reaction time was needed for 1e–1g,
compared to 1a–d. However, this was not seen for the nitro-de-
rivatives, 1h–i. Nitro groups are known to be efficient absorbers of
MW energy, and the observation suggests that specific microwave
effects are operating.
The main product of the reaction was 2l (88%) and formation of
the dimethyl acetal 7l,39 was also noticed (Scheme 4). Such side
products were not observed in fluorination of the other substrates.
OH
O
MeO
Ar
OMe
Ar
Ar
Ar
Ar
Ar
1l
7l
O
OH
MeO
Ar
OMe
F
F
F
3l
2l
F
The MW process gave a higher ketone to dimethyl acetal ratio
and higher amounts of a,a-difluorinated compounds than was the
case in the thermal process. It is assumed that fluorination by
F-TEDA-BF4 takes place on the enol form of the ketone, (Scheme 4).
O
Ar =
MeO OMe
Ar
F
O2N
F
F
NO2
4l
5l
As less
process, they are more available for further fluorination. This could
explain the elevated levels of the -difluoroketones in the
a-fluoroketones are trapped as dimethyl acetals in the MW
Scheme 4. Products and assumed reaction intermediates in fluorination of 1l.
The major challenge in the synthesis of 3l by this process resides in
the hydrolytic step. Somewhat surprisingly, fluorination continued
during hydrolysis, resulting in the formation of three difluorinated
a,a
microwave process as compared to the thermal method.
compounds, including 4l, 5l and a unknown compound (
d: 5.79,
3. Conclusion
JHF¼55.1 Hz).
The reaction progress for 1l can be rationalised by referring to
Scheme 4. When acetophenones are substituted with electron
withdrawing groups, the ketone/dimethyl acetal equilibrium po-
sition is shifted towards the dimethyl acetal side.40 This is espe-
cially pronounced in the case of 1l due to the presence of two nitro
groups. It can be assumed that fluorination takes place via the enol
form of the ketone, and due to the limited amount of the ketone 1l,
and thereby its enol, a reduction in the reaction rate is experienced.
A one-pot, two-step MW assisted fluorination of 1-aryletha-
nones has been developed. The main benefit of the MW strategy is
a reduction of the reaction time from several days to 1.5–2 h.
Moreover, a simplification of the dimethyl acetal cleavage step has
been developed, reducing the number of operations, chemical
consumption and time.
The method has its main advantage in the fluorination of
moderately deactivated acetophenones 1c–i, leading to the pro-
duction of the 1-aryl-2-fluoroethanones in 65–86% isolated yield.
Electron rich 1-arylethanones are not selectively fluorinated in
the side chain, but also forms fluoroaromatic derivatives. 1-(3-
Fluoro-4-methoxyphenyl)ethanone (1k) represents a borderline
case, where aromatic fluorination is starting to be suppressed.
Another limitation to the fluorination method is in the reaction
of 1-arylethanones having two strongly electron withdrawing
substituents. Although the fluorination takes place at a reduced
Once formed, the a-fluoroketone, 3l has an even higher tendency to
react with methanol, forming 2l. As evident from Table 3, the
amount of 3l in the reaction is very low, and further fluorination is
therefore difficult. When water is added, the equilibrium position is
shifted towards 3l and its enol form, enabling fluorination to con-
tinue. The reason why a,a-difluorination during hydrolysis appears
only for 3l is not understood.
Attempts to fluorinate 1l in water (80 W, 60 min) gave a com-
plex mixture and a conversion of approximately 30%. The domi-
nating products were 3l, 4l and the previous mentioned compound
with shift value of 5.79 ppm.
rate, the hydrolysis led to the formation of aliphatic
nated compounds, reducing the yield significantly.
a,a-difluori-
4. Experimental
4.1. General
2.3. Comparison of the MW and thermal fluorination
methods
A comparison of the MW and the thermal process, with respect
to reaction times and yields are shown in Table 4.
The 1-arylethanones 1a, 1g–h, 1l, and 1,3-dichloro-5,5-dime-
thylhydantoin were purchased from Fluka. SelectfluorÔ (F-TEDA-
BF4), 1c–f, 1j–k, and N-fluorobisbenzenesulfonimide were from
Aldrich. 1-(3-Nitrophenyl)ethanone (1i) was from Acros Organics,
while 1-(4-bromophenyl)-2-chloroethanone (6e) was from Sigma–
Aldrich. Methanol was from VWR (HPLC grade, 0.03% water). Col-
umn chromatography was performed using silica gel 60A from
The MW assisted reactions benefit from shorter reaction times;
fluorination proceeds in 60–120 min, whereas hydrolysis could be
performed in 15–30 min. The corresponding thermal fluorinations
required several days or weeks for complete conversion. The MW
assisted method was inferior to the thermal reaction for the se-
lective aliphatic fluorination of electron rich aromatic ketones
Fluka, pore size 40–63 mm. 1-(4-(Benzyloxy)phenyl)ethanone (1b)
(Entries 1–4), due to the formation of high levels of
difluoroketones.
a
,a
-
was prepared from 4-hydroxyacetophenone using benzyl chloride
and potassium carbonate in N,N-dimethylformamide as solvent.

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T.H. Krane Thvedt et al. / Tetrahedron 65 (2009) 9550–9556
4.2. Analyses
a white solid mp 49–51 ꢁC. 1H NMR (CDCl3)
7.15–7.21 (m, 2H) and 7.83–7.98 (m, 2H).
d
: 5.49 (d, J¼46.9, 2H),
NMR spectra were recorded with Bruker Avance DPX 400 oper-
ating at 400 MHz for 1H, 375 MHz for 19Fand 100 MHz for 13C. For 1H
and 13C NMR chemical shifts are inppm rel toTMS, while for 19F NMR
the shift values are relative to hexafluorobenzene. Coupling con-
stants are in hertz. MS (EI/70 eV) Finnigan MAT 95 XL. Accurate mass
determination (ESI) was performed on an Agilent G1969 TOF MS
instrument equipped with a dual electrospray ion source. Samples
were injected into the MS using an Agilent 1100 series HPLC and
analysis was performed as a direct injection analysis without any
chromatography. FTIR spectra were recorded on a Thermo Nicolet
Avatar 330 infrared spectrophotometer. All melting points are un-
corrected and measured by a Bu¨chi melting point instrument. The
microwave experiments were performed using an Anton Paar 3000
instrument with a magnetic stirrer device.
4.5.5. 1-(4-Bromophenyl)-2-fluoroethanone (3e)34,36. Compound 3e
was prepared as described in Section 4.3 starting with 1e (440 mg,
2.21 mmol). Fluorination was performed for 80 min, and hydrolysis
was done in 15 min. Purification by silica gel chromatography
(pentane/EtOAc, 85/15) gave 387 mg (1.78 mmol, 81%) of 3e as
a white solid mp 72–73 ꢁC. 1H NMR (CDCl3)
7.64 (m, 2H) and 7.77 (m, 2H).
d: 5.46 (d, J¼46.9, 2H),
4.5.6. 2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethanone (3f)36. Compound
3f was prepared as described in Section 4.3 starting with 1f (415 mg,
2.21 mmol). Fluorination was performed for 85 min, and hydrolysis
wasdonein25 min. Purificationbysilicagelchromatography(CH2Cl2)
gave 312 mg (1.52 mmol, 69%) of 3f as a white solid mp 36–37 ꢁC. 1H
NMR (CDCl3)
d: 5.52 (d, J¼46.8, 2H), 7.77 (m, 2H), 8.03 (m, 2H).
4.3. General procedure MW assisted fluorination
4.5.7. 4-(2-Fluoroacetyl)benzonitrile (3g)36. Compound 3g was
prepared as described in Section 4.3 starting with 1g (321 mg,
2.21 mmol), Fluorination was performed for 80 min, and hydrolysis
was done in 30 min. Purification by silica gel chromatography
(pentane/acetone, 7/3) gave 312 mg (1.90 mmol, 86%) of 3g as
To a Teflon reaction tube containing a magnetic stirrer bar 1-
arylethanone (2.21 mmol), SelectfluorÔ (4.42 mmol) and methanol
(5 mL) were added. The reaction chamber was sealed and treated at
80 W for the times specified in Table 4. After cooling, water (5 mL)
was added and the mixture was hydrolysed at 80 W with the re-
action times specified in Table 4. After cooling, water (15 mL) was
added and the mixture was extracted with CH2Cl2 (4ꢀ15 mL). The
dichloromethane layer was then washed with brine (15 mL), dried
over Na2SO4 and evaporated to dryness. The 1-aryl-2-fluo-
roethanones were purified by the methods specified for each single
compound.
a white solid mp 104–105 ꢁC. 1H NMR (CDCl3)
2H), 7.81 (m, 2H) and 8.02 (m, 2H).
d
: 5.51 (d, J¼46.8,
4.5.8. 2-Fluoro-1-(4-nitrophenyl)ethanone (3h)36. Compound 3h
was prepared as described in Section 4.3 starting with 1h (365 mg,
2.21 mmol), Fluorination was performed for 50 min, and hydrolysis
was done in 30 min. Purification by silica gel chromatography
(pentane/acetone, 7/3) gave 333 mg (1.81 mmol, 82%) of 3h as
a white solid mp 96–97 ꢁC. 1H NMR (CDCl3)
8.11 (m, 2H) and 8.35 (m, 2H).
d: 5.55 (d, J¼46.8, 2H),
4.4. Thermal fluorination in methanol
4.5.9. 2-Fluoro-1-(3-nitrophenyl)ethanone (3i)41. Compound 3h
was prepared as described in Section 4.3 starting with 1h (370 mg,
2.21 mmol), Fluorination was performed for 60 min, and hydrolysis
was done in 30 min. Purification by crystallisation from ethanol gave
293 mg (1.60 mmol, 72%) of 3h as a white solid mp 83–84 ꢁC.1H NMR
Thermal fluorination of the 1-arylethanones (1 equiv) in MeOH
using F-TEDA-BF4 (2 equivalents) was performed as described
previously.36
(CDCl3)
d
: 5.55 (d, J¼46.7, 2H), 7.72–7.77 (m, 1H), 8.27–8.29 (m, 1H),
4.5. 1-Aryl-2-fluoroethanones
8.48–8.51 (m, 1H), 8.75–8.76 (m, 1H). 13C NMR (CDCl3)
d: 83.9 (d,
J¼184.7),123.1 (d, J¼3.9),128.3,130.3,133.8 (d, J¼3.5),135.0 (d, J¼1.4),
4.5.1. 2-Fluoro-1-(4-methoxyphenyl)ethanone (3a)22,36. The iden-
tity of compound 3a was verified by comparison of 1H NMR shifts
148.5,192.0 (d, J¼17.0).19F NMR (CDCl3)
: ꢂ229.7 (t, J¼46.8). IR (neat,
d
cmꢂ1): 3101, 1712, 1630, 1537, 1438, 1239, 1080, 1021, 901, 730.
with a previous study.36 1H NMR (CDCl3)
d: 3.88 (s, 3H), 5.45 (d,
J¼47.2, 2H), 6.96 (m, 2H), 7.89 (m, 2H).
4.5.10. 2-Fluoro-1-(naphthalen-1-yl)ethanone (3j)42. For identifica-
tion purpose, compound 3j was synthesised from 1j (3.64 g,
21 mmol) via the trimethylsilyl enol ether as described by Fuglseth
etal.36 Theproduct waspurified bysilicagelcolumnchromatography
(CH2Cl2) giving an oil. A following crystallisation from EtOAc/pentane
yielded 1.10 g (5.83 mmol, 29%) of a white solid mp 44–45 ꢁC. The 1H,
13C and 19F NMR spectra corresponded with that reported.42 1H NMR
4.5.2. 1-(4-(Benzyloxy)phenyl)-2-fluoroethanone (3b)36. The iden-
tity of compound 3b was verified by comparison of 1H NMR shifts
with a previous study.36 1H NMR (CDCl3)
d: 5.14 (s, 2H), 5.46 (d,
J¼47.0, 2H), 7.02–4.04 (m, 2H), 7.36–7.43 (m, 5H) and 7.87–7.89
(m, 2H).
(CDCl3)
d
: 5.60 (d, J¼47.2, 2H), 7.50–7.61 (m, 2H), 7.65 (m,1H), 7.80 (m,
4.5.3. 2-Fluoro-1-phenylethanone (3c)19,36. Compound 3c was pre-
pared as described in Section 4.3 starting with 1c (265 mg,
2.21 mmol). Fluorination was performed for 60 min, and hydrolysis
was done in 15 min. Purification by silica gel chromatography
(pentane/EtOAc, 85/15) gave 198 mg (1.43 mmol, 65%) of 3c as
1H), 7.89 (m, 1H), 8.05 (d, J¼8.3, 1H), 8.71 (m, 1H).
4.5.11. 2-Fluoro-1-(3-fluoro-4-methoxyphenyl)ethanone (3k)22,36
.
Compound 3k was prepared as described in Section 4.3 starting
with 1k (370 mg, 2.21 mmol). Fluorination was performed
for 60 min, and hydrolysis was done in 15 min. Purification by
silica gel column chromatography (pentane/EtOAc, 5/2) gave
241 mg (1.30 mmol, 59%) of 3k as a white solid mp 84–85 ꢁC. 1H
a colourless oil. 1H NMR (CDCl3)
7.63 (m, 1H), 7.90 (m, 2H).
d: 5.53 (d, J¼47.0, 2H), 7.50 (m, 2H),
4.5.4. 2-Fluoro-1-(4-fluorophenylethanone) (3d)25,36. Compound 3d
was prepared as described in Section 4.3 starting with 1d (305 mg,
2.21 mmol). Fluorination was performed for 60 min, and hydrolysis
was done in 20 min. Purification by silica gel chromatography
(pentane/EtOAc, 85/15) gave 255 mg (1.63 mmol, 74%) of 3d as
NMR (CDCl3)
(m, 2H).
d
: 3.97 (s, 3H), 5.44 (d, J¼47.0, 2H), 7.04 (m, 1H), 7.70
4.5.12. 1-(3,5-Dinitrophenyl)-2-fluoroethanone (3l). Compound 3l
was prepared as described in Section 4.3 starting with 1l (464 mg,

T.H. Krane Thvedt et al. / Tetrahedron 65 (2009) 9550–9556
9555
2.21 mmol). Fluorination was performed for 120 min, and hydro-
lysis was done in 30 min. Compound 3l was purified by crystal-
lisation from chloroform giving 204 mg (0.89 mmol, 41%) of a white
silica gel chromatography (pentane/acetone, 85/15) gave 41 mg
(0.26 mmol, 12%) of 4c as an oil. 1H NMR data corresponded with
that reported previously.29 1H NMR (CDCl3)
7.54 (m, 2H), 7.68 (m, 1H), 8.08 (m, 2H).
d: 6.29 (t, J¼53.6, 1H),
solid, mp 111–112 ꢁC. 1H NMR (CDCl3)
d
: 5.55 (d, J¼47.0, 2H), 9.04–
9.05 (m, 2H), 9.28–9.30 (m, 1H). 13C NMR (CDCl3)
d
: 84.3 (d,
J¼186.9), 123.0, 128.3 (d, J¼4.9, 2C), 136.5 (d, J¼2.0), 149.0 (2C),
4.7.2. 2,2-Difluoro-1-(4-fluorophenyl)ethanone (4d)44. Compound
4d was prepared as described for 3d using MW heating. Purification
by silica gel chromatography (pentane/acetone, 85/15) gave 63 mg
190.7 (d, J¼18.4). 19F NMR (CDCl3)
: ꢂ227.3 (t, J¼46.9). HRMS (ESI):
d
227.0106 (calcd 227.0110, MꢂHþ). IR (neat, cmꢂ1): 3116, 3084, 2942,
1709, 1612, 1525, 1349, 1230, 1074, 975, 805, 736.
(0.36 mmol, 16%) of 4d as an oil. 1H NMR (CDCl3)
1H), 7.21 (m, 2H) and 8.13 (m, 2H).
d: 6.24 (t, J¼53.6,
4.5.13. 1-(3,5-Difluoro-4-methoxyphenyl)-2-fluoroethanone
(3n). Compound 3n was isolated after a thermal fluorination pro-
tocol as described previously,36 starting with 1k (1.49 mg,
8.84 mmol). Fluorination was performed for 96 h., while hydrolysis
in TFA/water/CHCl3 was performed for 3.5 h. The by-product, 3n,
was isolated by silica gel chromatography (pentane/EtOAc, 7/3)
4.7.3. 1-(4-Bromophenyl)-2,2-difluoroethanone (4e)43. Compound
4e was prepared as described for 3e using MW heating. Purification
by silica gel chromatography (pentane/acetone, 85/15) gave 85 mg
(0.36 mmol, 16%) of 4e as an oil. 1H NMR data corresponded with
that reported previously.43 1H NMR (CDCl3)
7.69 (m, 2H), 7.95 (m, 2H).
d
: 6.24 (t, J¼53.5, 1H),
giving 14 mg (0.07 mmol, 1%) of a colourless oil. 1H NMR (CDCl3)
d:
4.14 (t, J¼1.8, 3H), 5.40 (d, J¼46.9, 2H), 7.47–7.52 (m, 2H). 13C NMR
(CDCl3)
d
: 61.7 (t, J¼4.2), 83.6 (d, J¼184.4), 112.6 (ddd, J¼3.9, 7.4,
4.7.4. 2,2-Difluoro-1-(4-trifluoromethylphenyl)ethanone (4f). Compound
4f was prepared as described for 3f using MW heating. Purification
by silica gel chromatography (CH2Cl2) gave 87 mg (0.38 mmol, 17%)
16.6, 2C), 117.2 (d, J¼1.4), 141.6, 154.9 (dd, J¼5.7, 256.4, 2C), 190.7 (d,
J¼16.0). 19F NMR (CDCl3)
: ꢂ127.2 (d, J¼8.0), ꢂ229.2 (t, J¼46.9).
d
HRMS (ESI): 205.0473 (calcd 205.0471, MþHþ). IR (neat, cmꢂ1):
of 4f as an oil. 1H NMR (CDCl3)
and 8.21 (m, 2H).
d: 6.27 (t, J¼53.4, 1H), 7.81 (m, 2H)
2946, 2847, 1708, 1517, 1432, 1330, 1081, 1040, 992, 707.
4.6. 1-Aryl-1,1-dimethoxyethylfluorids (2)
4.7.5. 2,2-Difluoro-1-(4-nitrophenyl)ethanone (4h)28. Compound
4h was synthesised as described by Peng et al.28 starting with 1h
(2.07 g, 12.53 mmol). The crude product obtained (1.65 g, contam-
inated with 3h) had an 1H NMR spectra, which corresponded well
Seven 1-aryl-2,2-dimethoxyethylfluorides were characterised in
the previous study.36 The identity of the dimethyl acetals 2d and 2n
was assumed from their 1H NMR shifts and coupling constants, and
their conversion to the corresponding 1-aryl-2-fluoroethanones by
hydrolysis.
with that reported. 1H NMR (CDCl3)
2H), 8.39 (m, 2H).
d: 6.28 (t, J¼53.3, 1H), 8.27 (m,
4.7.6. 2,2-Difluoro-1-(naphthalen-1-yl)ethanone (4j)42. Compound
4j was synthesised based on the method reported by Verniest
et al.30 starting with 1j (2.30 g. 13.54 mmol). Compound 1j was first
converted to its corresponding methyl imine, followed by fluori-
nation using N-fluorobisbenzenesulfonimide. The difluorinated
imine formed was hydrolysed using HCl. This gave after purification
by silica gel column chromatography (CH2Cl2) 1.34 g, (6.50 mmol,
48%) of a pale yellow oil. The 1H, 13C and 19F NMR spectra corre-
4.6.1. 1-(2-Fluoro-1,1-dimethoxyethyl)-3-nitrobenzene (2i). Compound
2i was synthesised from 1i (370 mg, 2.21 mmol) by MW fluorina-
tion at 80 W for 60 min, omitting the hydrolytic step. Purification
by silica gel chromatography (pentane/acetone, 7/3), gave 137 mg
(0.60 mmol, 27%) of a slightly yellowish solid, mp 57–59 ꢁC. 1H NMR
(CDCl3)
d
: 3.30 (s, 6H), 4.52 (d, J¼47.0, 2H), 7.58 (m, 1H), 7.86 (m,
1H), 8.22 (m, 1H) and 8.42 (m, 1H). 13C NMR (CDCl3)
d
: 49.3 (2C),
82.5 (d, J¼178.4), 99.9 (d, J¼20.8),122.8 (d, J¼1.1),123.6,129.3,133.5
sponded with that reported.42 1H NMR (CDCl3)
d
: 6.42 (t, J¼53.9,
(d, J¼1.1), 140.8, 148.5. 19F NMR (CDCl3)
d
: ꢂ231.7 (t, J¼47.0). HRMS
1H), 7.54–7.63 (m, 3H), 7.68 (m, 1H), 7.91 (d, J¼8.0, 1H), 8.14 (d,
(ESI): 252.0643 (calcd 252.0648, MþNaþ). IR (neat, cmꢂ1): 3097,
J¼8.0, 1H), 8.19 (m, 1H), 8.85 (d, J¼8.0, 1H).
1543, 1348, 1070, 730, 695.
4.8. 1-Aryl-2-chloroethanones (6)
4.6.2. 1-(2-Fluoro-1,1-dimethoxyethyl)-3,5-dinitrobenzene
(2l).
Compound 2l was synthesised from 1l (464 mg, 2.21 mmol) by MW
fluorination at 80 W for 120 min, omitting the hydrolytic step.
Purification by silica gel chromatography (pentane/acetone, 7/3),
gave 157 mg (0.57 mmol, 26%) of a slightly yellowish solid, mp 87–
Trace impurities of 1-aryl-2-chloroethanoes were observed af-
ter most fluorinations. The identity of selected compounds was
verified by isolation or synthesis.
91 ꢁC. 1H NMR (CDCl3)
d
: 3.34 (s, 6H), 4.56 (d, J¼46.8, 2H), 8.72 (d,
4.8.1. 1-(4-(Benzyloxy)phenyl)-2-chloroethanone (6b)45. 1-(4-Ben-
zyloxyphenyl)ethanone (1b) (5.49 g, 19.0 mmol) and p-TsOH
(2.31 g, 12.1 mmol) were suspended in methanol (500 mL) at 40 ꢁC.
Then 1,3-dichloro-5,5-dimethylhydantoin (3.59 g, 18.2 mmol) was
added in portions over 1 h, followed by agitation of the reaction
mixture at 40 ꢁC for 22 h. Methanol was then distilled off until
crystallisation started, followed by slow addition of water (200 mL).
The suspension formed was then stirred for 45 min followed by
isolation of the solid material. The crude product was recrystallised
from EtOAc/ethanol. This gave 4.03 g (63%) of a white solid, mp
111–112 ꢁC (Lit.45 109–110 ꢁC). 1H and 13C NMR spectra corre-
J¼2.1, 2H) and 9.05 (t, J¼2.1, 1H). 13C NMR (CDCl3)
d: 49.5 (2C), 81.7
(d, J¼178.7), 99.6 (d, J¼21.2), 119.0, 127.9 (d, J¼1.1, 2C), 143.5, 148.6
(2C). 19F NMR (CDCl3)
1528, 1347, 1064, 703.
d
: ꢂ232.2 (t, J¼46.9). IR (neat, cmꢂ1): 3086,
4.7. 1-Aryl-2,2-difluoroketones (4)
The 1H NMR chemical shift and the coupling constants of the
difluoromethylene groups in the
a,a-difluoroketones were com-
pared by that reported previously for 4a,29,43 4c,29 4e,43 and 4h.28
Selected compounds were isolated or synthesised. The compounds
4i and 4j could not be isolated in a sufficiently pure form for
characterisation.
sponded with that reported.45 1H NMR (CHCl3)
d: 4.62 (s, 2H), 5.13
(s, 2H), 7.01 (m, 2H), 7.30–7.42 (m, 5H), 7.92 (m, 2H).
4.8.2. 1-(4-Bromophenyl)-2-chloroethanone (6e)37. The identity of
6e was verified by HPLC co-eluation with a commercial sample of
4.7.1. 2,2-Difluoro-1-phenylethanone (4c)29. Compound 4c was
prepared as described for 3c using MW heating. Purification by
6e. Column: Symmetry C8 3.5
mm, 4.6ꢀ150 mm, (Waters Corp.,

9556
T.H. Krane Thvedt et al. / Tetrahedron 65 (2009) 9550–9556
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amine (30/70/0.1, vol%) after 70 min; flow rate: 1.0 mL/min;
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(DMSO-d6) d: 5.28 (s, 2H), 7.94 (m, 2H), 8.17 (m, 2H).
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4.8.4. 2-Chloro-1-(4-nitrophenyl)ethanone (6h)37. Compound 6h
were obtained after a thermal fluorination a of 1h (2.92 g,
17.68 mmol) in methanol for 11 days, followed by acetal cleavage
using hydrochloric acid (10%, 20 mL) in THF (80 mL) at 65 ꢁC over-
night. After work-up, the resulting solid was crystallised from CHCl3.
The resulting mother liquor was then purified by silica gel chro-
matography (CHCl3) yielding 30 mg (0.02 mmol, 1%) of an off-white
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reported.47 1H NMR (CDCl3)
d: 4.72 (s, 2H), 8.15 (m, 2H), 8.36 (m, 2H).
Acknowledgements
Norwegian University of Science and Technology is acknowledged
for a Ph.D. grant. Tor-Arne Krakeli is thanked for his contribution.
36. Fuglseth, E.; Krane Thvedt, T. H.; Førde Møll, M.; Hoff, B. H. Tetrahedron 2008,
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