Micellar-system-mediated direct fluorination of ketones in water

Article abstract of DOI:10.1055/s-0028-1087924

A micellar system was developed and applied for direct regioselective fluorination of a variety of cyclic and acyclic ketones to α-fluoroketones in water as reaction medium with Selectfluor F-TEDA-BF₄ as fluorinating reagent. The inexpensive ionic amphiphile sodium dodecyl sulfate (SDS) was found to be an excellent promoter for fluorofunctionalization of hydrophobic ketones without prior activation or use of acid catalysts. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087924

LETTER
589
Micellar-System-Mediated Direct Fluorination of Ketones in Water
D
irec
t
Fluorination
a
of
K
etone
j
s
in
W
ater Stavber,a Marko Zupan,a Stojan Stavber*b
a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Laboratory of Organic and Bioorganic Chemistry, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia
Fax +386(1)423-5400; E-mail: stojan.stavber@ijs.si
b
Received 12 November 2008
Dedicated to Professor Branko Stanovnik on the occasion of his 70th birthday
organic substrates with water, which is a result of hydro-
phobic interactions, is a potential obstacle to perform or-
ganic reactions in water. Increasing the solubility of
substrates and reagents in water is of crucial importance to
Abstract: A micellar system was developed and applied for direct
regioselective fluorination of a variety of cyclic and acyclic ketones
to a-fluoroketones in water as reaction medium with Selectfluor
F-TEDA-BF4 as fluorinating reagent. The inexpensive ionic am-
phiphile sodium dodecyl sulfate (SDS) was found to be an excellent enable reactions in water, although some reactions under
promoter for fluorofunctionalization of hydrophobic ketones with-
‘on water’ conditions when the organic reactants were in-
soluble in the aqueous phase have also been presented.8
out prior activation or use of acid catalysts.
Key words: ketones, halogenation, micelles, F-TEDA-BF4, water
Hydrophobic interactions (HI) between the apolar parts of
organic molecules in water is a well-studied area of phys-
icoorganic chemistry, and it has been known for a long
Fluorine-containing organic compounds have become
very important molecules in several branches of industry
and medicine1 because the special nature of fluorine in-
duces beneficial changes in their physicochemical proper-
ties, metabolic stability, selective reactivities, and
enhanced binding interactions. Potential drug candidates
with one or even more fluorine atoms, especially fluori-
nated aromatics and heterocyclic compounds, on one hand
and fluoroaliphatic, fluoroallylic molecules one the other,
have become commonplace.2 Synthetic methods for
selective and effective introduction of a fluorine atom into
organic molecules have made enormous strides since the
first report in 1863 of the fluoride displacement of halo-
gens.3 Synthesis of organofluorine compounds include
nucleophlilic, electrophilic, and also radical forms of fluo-
rine reagents which are usually commercially available,
easy to handle, and no longer require specialized labora-
tory equipment. Very important progress was made by the
introduction and broad synthetic application of electro-
philic fluorine reagents containing an N–F bond as effec-
tive, selective, and mild fluorinating reagents.4 Selectfluor
F-TEDA-BF4 became one of the most important members
of the class of N–F reagents for introduction of fluorine
into organic compounds under mild reaction conditions.
This can take place in an ordinary chemical research lab-
oratory or on the multiton-per-year scale to produce
chemicals for industrial applications.5
time that HI can have significant influence on organic
reactions in water.9 Hydrophobic effect usually makes a
transformation of organic molecules in water impossible,
but on the other hand, Diels–Alder reactions are acceler-
ated in water compared to organic solvents.10 To succeed
in performing organic reactions in water several potential
approaches are possible: using antihydrophobic agents
like cosolvents or salts,11a sonication of a heterogeneous
mixture,11b or addition of amphiphiles to form micellar ag-
gregates or colloidal dispersions.11c,d
Reactions in micellar systems have considerably extended
organic chemistry in water, and extraordinary selectivities
and activities can be achieved through the addition of in-
expensive amphiphiles that self-associate into micelles,
accommodate insoluble organic substrates within hydro-
phobic cores, and consequently very often accelerate the
rate of reaction. The size and structure of the aggregates
formed depend on many parameters: the nature of the am-
phiphiles and their concentration, temperature, pH, etc.,
and through these parameters it is possible to regulate the
micellar effect.12
In our continuing interest in developing synthetic proto-
cols for selective halogenation of organic molecules in or
on water,13 we now report direct fluorination of a broad
structural range of ketones using Selectfluor F-TEDA-
BF4 in micellar aqueous systems.
The position a to a carbonyl moiety seems to be the most
strategic one for the introduction of a fluorine atom into
ketones, but when using electrophilic fluorinating re-
agents, prior activation through metal enolate anions, enol
ethers, enamines or imines has for a long time been the
normal synthetic procedure.14 However, we demonstrated
that direct fluorination of ketones could be effectively and
selectively accomplished in MeCN15a or MeOH as sol-
vents,15b,c while in pure water the efficiency of the trans-
formation was found to be lower.15d With the goal of
In line with the principles of green and sustainable chem-
istry, the preferability of safer alternative reaction media
in place of volatile or toxic organic solvents is one of the
major and still challenging issues.6 The use of water as the
reaction medium in organic synthesis is no longer an un-
known issue,7 but in some cases the incompatibility of
SYNLETT 2009, No. 4, pp 0589–0594
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x.
x
x.
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Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087924; Art ID: G36008ST
© Georg Thieme Verlag Stuttgart · New York

590
G. Stavber et al.
LETTER
O
O
H
HO
w
x OH
O
Me
Br–
O
10
N+ Me
O
O
O
OH
O
Me
y
CTAB (3)
R
z
Triton X-100 (1)
Tween 20 (2) x + y + z + w = 20
R = C11H23
O
OR
OSO3– Na+
RO
N+
–
MeOSO3
Me
SDS (5)
Prapeagen 4317 (4)
R = C18H23CO
RO
Figure 1 Structures of nonionic and ionic amphiphiles screened
BF4,17 but choosing cationic amphiphile 4 with the
MeOSO3 anion did not appreciably improve the efficien-
Table 1 The Effect of Type and Structure of the Amphiphile on the
Fluorination of Indane-1-one (6) with F-TEDA-BF4 in Watera
–
cy of the transformation (entry 5). The anionic amphiphile
sodium dodecyl sulfate (SDS, 5) was found to be the right
choice and quantitative conversion of indan-1-one (6) to
2-fluoro-indan-1-on (7) was obtained (entry 6) and SDS
(5) was then used as the amphiphile in all further experi-
ments.
O
O
F
SelectfluorTM F-TEDA-BF4
amphiphile, H2O, 80 °C
6
7
Entry
Amphiphile
pure H2O
Conversion of 6 into 7 (%)
The hydrophobicity of the substrate on the one hand, and
a sufficient degree of enolization on the other, could be
the main factors regulating the efficiency of direct fluori-
nation of ketones in water. Diminishing hydrophobic
interactions between the apolar parts of the substrate and
water and enabling reaction conditions favorable for eno-
lization of ketones seem to be the main tasks in order to
obtain the highest degree of direct fluorination of the start-
ing material. We thus chose the two test compounds
indane-1-one (6) and its acyclic analogue 1-phenylpro-
pan-1-one (8) and studied the effect of the concentration
of SDS (Table 2) on the direct fluorination of these two
compounds. These should have similar hydrophobic char-
acteristics, but different reactivity towards electrophilic
fluorination,15a which can be attributed to their different
degree of enolization.18 Amounts of SDS below its critical
micelle concentration (CMC)12a had no appreciable effect
on transformations of 6 to 7 or 8 to 9 in comparison with
the reaction in pure water (entries 1–3), but the efficiency
of fluorination increased with a higher concentration of
SDS more rapidly (entries 4–6), and quantitative conver-
sion into 2-fluoroindan-1-one (7) was established for a 0.1
M SDS aqueous solution (entry 6). For transformation of
less reactive 1-phenyl-propan-1-on (8) to 2-fluoro-1-phe-
nylpropan-1-one (9), a 0.2 M aqueous solution was found
to be optimal (entry 7). These results indicate that for less
enolizable ketones stronger disruption of hydrophobic in-
teractions is necessary in order to obtain optimal reaction
conditions for direct fluorination in aqueous media. The
regulation of both effects could also be accomplished by
cosolvents, but as evident from the data in Table 2 (entries
8–13), this solution could be applied in the case of indan-
1-one (6), but not for its acyclic analogue 1-phenylpro-
pan-1-one (8).
1
2
3
4
5
6
58
38
Triton X-100 (1)
Tween 20 (2)
CTAB (3)
60
28
Prapeagen 4317 (4)
SDS (5)
62
100
a Reaction conditions: 6 (1 mmol), F-TEDA-BF4 (1.1 mmol), 2.8% aq
soln of amphiphile (5 mL), 80 °C, stirring 12 h.
developing simple and environmentally friendly synthetic
protocols for direct fluorination of ketones, we found a so-
lution using a micellar aqueous system.
We chose nonionic and ionic amphiphiles 1–5 (Figure 1),
which micellization and its mechanism in aqueous solu-
tion were already explored,16 and studied their effect on
the direct transformation of indan-1-one (6) to 2-fluoro-
indan-1-on (7) using Selectfluor F-TEDA-BF4 in aqueous
reaction media. The reactions were carried out in 5 mL of
a 2.8% aqueous solution of amphiphiles 1–5 at 80 °C, and
after isolation of crude products by extraction with diethyl
ether, the conversion of starting ketone 6 to 7 was verified
by NMR analysis. From the results collected in Table 1 it
is obvious that direct fluorination of 6 in aqueous media
was affected by the presence and the nature of the am-
phiphile used. Nonionic amphiphiles Triton X-100 (1, en-
try 2) and Tween 20 (2, entry 3) proved to be less efficient
and also structurally unsuitable because fluorination of
the aromatic part of Triton X-100 was also detected. The
cationic amphiphile cetyltrimethylammonium bromide
(CTAB, 3, entry 4) proved to be inappropriate since an-
ionic Br– part of the surfactant could react with F-TEDA-
Synlett 2009, No. 4, 589–594 © Thieme Stuttgart · New York

LETTER
Direct Fluorination of Ketones in Water
591
Table 2 Effect of the Concentration of SDS or Cosolvent on the
one (13) in a relative ratio of 1:1.5 (entries 3 and 4). In the
case of 4,4-dimethylcyclohex-2-enone (14, entry 5),
which possesses two potential reactive centers for fluoro-
functionalization, 6-fluoro-4,4-dimethylcyclohex-2-en-
one (15) was selectively formed (entry 5). Cycloal-
kanones having different ring sizes (16a–e, entries 6–10)
were also readily converted to the corresponding a-fluoro
derivatives 17a–e in high yields, but in these cases the for-
mation of 5–10% of symetrical a,a¢-difluoro derivatives
was detected in the crude reaction mixtures. We also ap-
plied this methodology using a 0.1 M SDS aqueous micel-
lar system for direct fluorination of the a-carbonyl moiety
in 5a-cholestan-3-one (18, entry 11) as a representative
example of steroids forming 2a-fluoro-5a-cholestan-3-
one (19) without prior activation.20
Fluorination of Cyclic and Acyclic Phenyl Alkyl Ketonesa
O
O
F
6
7
F-TEDA-BF4
H2O
SDS or cosolvent
80 °C
F
O
O
9
8
We further checked the reactivity of various acyclic
ketones for fluorofunctionalization in the SDS aqueous
micellar system. Regioselective fluorination was ob-
served in the case of 1-phenylpropan-2-one (20) in the 0.1
M SDS aqueous system forming 1-fluoro-1-phenylpro-
pan-2-one (21, entry 12), while in the case of its more hy-
drophobic analogue 1,1-diphenylpropan-2-one (22,
entries 13 and 14), a 0.2 M SDS aqueous solution was nec-
essary for conversion into 1-fluoro-1,1-dipehylpropan-2-
one (23). The method was found to be less efficient in the
case of 1-phenylethanone (24), since not more than 45%
conversion to 2-fluoro-1-phenylethanone (25) could be
obtained even using a higher concentration of SDS (en-
tries 15 and 16). The insufficient enolization of the methyl
group under such reaction conditions could be the reason
for this result. This investigation came to an end when
phenyl-substituted alkylmethyl ketone 4-phenylbutan-2-
one (26) was selectively transformed into 3-fluoro-4-phe-
nylbutan-2-one (27) in high yield (entry 17). The method-
ology of the SDS aqueous micellar system also proved to
be efficient for direct fluorination of dialkyl-substituted
ketones. Octan-2-one (28) was converted into 3-fluoro-
octan-2-one (29, entry 18) and nonan-5-one (30) to 4-fluo-
rononan-5-one (31) (entries 19 and 20).
Entry SDS (mol/L) Cosolvent (vol%)
Conversion (%)b
6 into 7
58
8 into 9
18
1
2
pure H2O
–
4.0·10–3
–
63
25
3
8.1·10–3,c
–
69
30
4
2.0·10–2
–
83
43
5
4.0·10–2
–
89
53
6
10–1
–
100 (91)
100
100
100
100
100
100
100
71
7
2.0·10–1
–
90 (77)
20
8
–
–
–
–
–
–
MeOH (10)
MeOH (50)
MeOH (80)
MeCN (10)
MeCN (50)
MeCN (80)
9
74
10
11
12
13
45
15
56
20
a Reaction conditions: ketone (1 mmol), F-TEDA-BF4 (1.1 mmol),
H2O with SDS or H2O with cosolvent (5 mL), 80 °C, stirring 12 h for
6 and 24 h for 8.
In conclusion, we have developed an efficient and envi-
ronmentally benign synthetic protocol for direct fluorina-
tion of a broad structural range of ketones in water as the
reaction medium using Selectfluor F-TEDA-BF4. It was
shown that the use of the SDS micellar aqueous system is
the key factor diminishing the hydrophobicity of sub-
strates and enabling formation of a sufficient amount of
the enol form, which could be the main factors in efficient
fluorination. The results demonstrated that the efficiency
of direct fluorination of ketones in water was significantly
accelerated by the concentration of SDS, and the 0.1 M
SDS aqueous system was found to be usually optimal for
efficient fluorofunctionalization, while higher concentra-
tions (0.2 M SDS) were necessary for more hydrophobic
and/or less enolizable substrates. The reaction protocol in-
volving Selectfluor F-TEDA-BF4 as the fluorine transfer
source in the SDS aqueous micellar system gave positive
results regarding the regioselectivity of fluorination of
benzylmethyl or alkylmethyl ketones and also enabled
b Conversion was determined from 1H NMR, the values in parenthe-
ses refer to isolated pure products purified on a silica column using
CH2Cl2–n-hexane (9:1).
c Critical micelle concentration (CMC) at 25 °C.12a
Encouraged by these results and the experimental in-
sights, we evaluated the method on a variety of ketones,
especially focusing on their structural and hydrophobic
differences.19 The results of these efforts are presented in
Table 3. The evaluation started with cyclic ketones (en-
tries 1–10) and their excellent reactivity for direct fluori-
nation was established. 3,4-Dihydro-2H-naphthalen-1-
one (10a) and 6,7,8,9-tetrahydrobenzocyclohepten-5-one
(10b) were selectively transformed into a-fluoro deriva-
tives 11a,b (entries 1 and 2) with high yields, while a 0.2
M aqueous solution of SDS was necessary for efficient
transformation of 4-tert-butylcyclohexanone (12) to a
mixture of cis- and trans-4-tert-butyl-2-fluorocyclohexan-
Synlett 2009, No. 4, 589–594 © Thieme Stuttgart · New York

592
G. Stavber et al.
LETTER
a
Table 3 Direct Fluorination of Ketones in SDS Aqueous Micellar System Using Selectfluor F-TEDA-BF4
Entry
Ketone
SDS (M) Product
Yield (%)d
O
O
1
2
10a (n = 2)
10b (n = 3)
0.1
11
90
86
F
(CH2)n
F
0.1
(CH2)n
3
4
0.1
13
52b
83b
12
14
O
0.2
O
O
5
0.1
15
80
O
F
6
7
8
9
10
16a (n = 3)
16b (n = 4)
16c (n = 6)
16d (n = 8)
16e (n = 11)
0.1
0.1
0.1
0.1
0.1
17a
17b
17c
17d
17e
86c
82c
87
O
O
F
86c
92c
(CH2)n
(CH2)n
C6H13
C6H13
H
H
11
12
18
20
0.1
0.1
19
21
70
93
H
H
F
H
H
O
O
H
H
F
Ph
Ph
O
O
O
O
13
14
0.1
0.2
60
87
22
24
26
23
25
27
Ph
Ph
Ph
Ph
F
O
15
16
O
0.1
0.2
30
40
F
Ph
Ph
Ph
Ph
O
O
17
18
0.1
0.1
83
88
F
O
O
28
30
29
31
F
F
O
19
20
0.1
0.2
53c
80c
O
a Reaction conditions: ketone (1 mmol), F-TEDA-BF4 (1.1 mmol), 0.5–1 mmol of SDS in 5 mL of H2O, 80 °C, 6–24 h until the reagent was
consumed.
b A mixture of cis- and trans-products in 1:1.5 ratio.
c Symmetrical a,a¢-difluoro products (5–10%) were also observed by 1H NMR and also detected by MS analysis of crude reaction mixtures.
d Low conversions of starting ketones to fluorinated products were observed after reactions performed in pure water.
fluorination of less soluble and reactive ketones in water tivation of hydrophobic molecules21 make the present
without further activation or use of catalysts. The use of method attractive, particularly in the field of the halogena-
water as an environmentally benign solvent, the easy tion of organic molecules with emphasis on the principles
workup, and methodology of ‘micellar catalysis’12b for ac- of green chemistry.
Synlett 2009, No. 4, 589–594 © Thieme Stuttgart · New York

LETTER
Direct Fluorination of Ketones in Water
593
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Acknowledgment
We are grateful to the staff of the National NMR Centre at the Na-
tional Institute of Chemistry, Ljubljana, Slovenia and the staff of the
Mass spectroscopy Centre at the ‘Jožef Stefan’ Institute. The Slove-
nian Research Agency is thanked for financial support (program P1-
0134).
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(19) General Procedure for the Direct Fluorination of
Ketones in SDS Aqueous Micellar System
Ketone (1 mmol) was placed in a glass flask (25 mL)
equipped with a magnetic stirrer. Then, H2O (5 mL) was
added and stirred for a few minutes. An appropriate amount
of SDS (144 mg, 0.5 mmol or 288 mg, 1 mmol; see Table 3)
was then added to the heterogeneous reaction system and
heated to 80 °C during rapid stirring. When the reaction
system reached 80 °C, F-TEDA-BF4 (390 mg, 1.1 mmol)
was added in two portions over an interval of 1 h, and stirred
and held at 80 °C until the KI test showed consumption of
the fluorinating reagent. When reaction was complete, the
reaction system was cooled to r.t., and the resulting
suspension was extracted with Et2O (2 × 15 mL). The
combined ether phases were dried over anhyd Na2SO4. After
the removal of the solvent under reduced pressure, the crude
products obtained were identified with 1H NMR, 19F NMR,
and MS analysis and purified by silica gel column
chromatography or preparative TLC (SiO2, CH2Cl2, and a
few drops of EtOH) to afford pure a-fluoro ketones. The
spectroscopic data of the products were in agreement with
those reported in the literature.
Spectroscopic Data for Representative Compounds
1-Fluoro-1-phenylpropan-2-one22 (21)
Liquid product. 1H NMR (300 MHz, CDCl3): d = 2.23 (d,
J = 4.0 Hz, 3 H, Me), 5.68 (d, J = 48.7 Hz, 1 H, CHF), 7.40
(br s, 5 H, ArH). 19F NMR (285 MHz, CDCl3): d = –183.14
(dq, J = 48.7, 4.0 Hz). 13C NMR (76.2 MHz, CDCl3):
d = 25.13 (Me), 95.84 (d, J = 187.8 Hz, C-1), 126.00 (d,
J = 7.0 Hz), 128.9, 129.36 (d, J = 2.3 Hz), 133.94 (d, J =
20.6 Hz), 204.55 (d, J = 26.7 Hz, CO). MS (EI, 70eV):
m/z (%) = 152 (6) [M+], 110 (10), 109 (100), 83 (20).
1-Fluoro-1,1-diphenyl-propan-2-one23 (23)
(11) (a) Breslow, R. Acc. Chem. Res. 2004, 37, 471. (b) Luche,
J. L. Synthetic Organic Sonochemistry; Plenum Press: New
York, 1998. (c) Tascioglu, S. Tetrahedron 1996, 52, 11113.
(d) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35,
209.
Mp 58.5–60.0 °C. 1H NMR (300 MHz, CDCl3): d = 2.41 (d,
J = 5.9 Hz, 3 H, Me), 7.37 (br s, 10 H, ArH). 19F NMR (285
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G. Stavber et al.
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MHz, CDCl3): d = –143.62 (q, J = 5.9 Hz). 13C NMR (76.2
MHz, CDCl3): d = 26.71 (Me), 102.17 (d, J = 185.8 Hz,
C-1), 126.64 (d, J = 7.4 Hz), 128.34, 128.77 (d, J = 2.0 Hz),
137.54 (d, J = 22.8 Hz), 206.43 (d, J = 32.7 Hz, CO).
MS (EI, 70eV): m/z (%) = 185 (100) [M+ – COMe], 151 (11).
3-Fluoro-4-phenylbutan-2-one24 (27)
C-3), 127.10, 128.57, 129.49, 135.28, 209.98 (d, J = 26.7
Hz, CO). MS (EI, 70eV): m/z (%) = 166 (100) [M+], 146
(100), 123 (15), 91 (77), 77 (41).
(20) Thomas, M. G.; Suckling, C. J.; Pitt, A. R.; Suckling, K. E.
J. Chem. Soc., Perkin Trans. 1 1999, 3191.
(21) The graphical abstract drawing was inspired by that of the
article: Manabe, K.; Iimura, S.; Sun, X.-M.; Kobayashi, S.
J. Am. Chem. Soc. 2002, 124, 11971.
(22) Stavber, S.; Zupan, M. J. Org. Chem. 1987, 52, 5022.
(23) Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1991, 56,
4925.
Liquid product. 1H NMR (300 MHz, CDCl3): d = 2.13 (d,
J = 4.9 Hz, 3 H, Me), 3.01–3.21 (m, 2 H, CH2), 4.93 (ddd,
J = 48.5, 6.0, 3.0 Hz, 1 H, CHF), 7.21–7.34 (m, 5 H, ArH).
19F NMR (285 MHz, CDCl3): d = –188.66 (dtq, J = 48.5,
23.2, 5.0 Hz). 13C NMR (76.2 MHz, CDCl3): d = 26.42
(Me), 38.10 (d, J = 20.6 Hz, C-4), 95.89 (d, J = 187.3 Hz,
(24) Welch, J. T.; Seper, K. W. J. Org. Chem. 1988, 53, 2991.
Synlett 2009, No. 4, 589–594 © Thieme Stuttgart · New York

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