Direct α-fluorination of ketones using N-F reagents

Article abstract of DOI:10.1055/s-2002-35625

The use of 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Accufluor NFTh) as a fluorine atom transfer reagent and methanol as solvent enabled direct regiospecific fluorofunctionalization of the α-carbonyl position in ketones w

Full text of DOI:10.1055/s-2002-35625

SPECIAL TOPIC
2609
Direct -Fluorination of Ketones Using N F Reagents
D
irec
t
-
Fluor
t
o
of
K
etones jan Stavber,* Marjan Jereb, Marko Zupan
Laboratory for Organic and Bioorganic Chemistry, ‘Jozef Stefan’ Institute and Department of Chemistry, University of Ljubljana,
Jamova 39, 1000 Ljubljana, Slovenia
Fax +386(1)4773811; E-mail: stojan.stavber@ijs.si
Received 22 July 2002
sis. In our continued interest in this field of fluoroorganic
chemistry we now report some results dealing with site-
selective fluorination of ketones using N–F reagents.
Abstract: The use of 1-fluoro-4-hydroxy-1,4-diazoniabicyc-
lo[2.2.2]octane bis(tetrafluoroborate) (AccufluorTM NFTh) as a
fluorine atom transfer reagent and methanol as solvent enabled di-
rect regiospecific fluorofunctionalization of the -carbonyl position
in ketones without prior activation of the target molecules. Methoxy
or hydroxy substituted derivatives of 1-indanone, 1-tetralone and
oxo derivatives of thiophene, benzo[b]thiophene, benzofuran and
benzopyran were regiospecifically transformed to the correspond-
ing -fluoro derivatives in high yield, while 2 -fluoro-5 -
cholestan-3-one (28) and 16 -fluoro-3 -hydroxy-5 -androstan-17-
one (30) were regio- and stereospecifically obtained starting direct-
ly from the corresponding keto steroids.
The carbon atom to the carbonyl group seems to be the
most strategic one for fluorination.5 As an electron-rich
site, this reactive center needs electron-deficient sources
of the fluorine moiety. N–F reagents are actually conve-
nient compounds for this purpose as has been demonstrat-
ed in regard to the regio as well as the stereoselectivity of
fluorofunctionalisation.2,3,6 As with other electrophilic
fluorinating reagents, when using N–F reagents, prior ac-
tivation of the carbonyl substrate, through enolate anions
or enol ethers was reported to be necessary for effective
fluorination of the -carbonyl position, except for suffi-
ciently activated 1,3-dicarbonyl substrates, where direct
fluorofunctionalization could be achieved. On the other
hand, direct -fluorination of a comprehensive range of
ketones was reported to be effective by using 1-fluoro-4-
hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetra-
fluoroborate) (AccufluorTM NFTh) as fluorinating re-
agent,7 while the regioselectivity of the reaction could be
regulated by the solvent.8 In order to check the related ef-
fects of other commercially available and commonly used
N–F reagents, we chose 1-tetralone as a model substrate
and tried to fluorinate it directly using a representative
material from each class of N–F reagents. By keeping the
reaction time and temperature constant, the N–F reagent
and solvent as variable reaction parameters, the indicative
results collected in Table 1 were obtained. In acetonitrile,
N-fluoro-2,6-dichloropyridinium tetrafluoroborate (FP-
B800; 1) as a representative from the class of N-fluoro-
pyridinium salts, readily transformed 1-tetralone to 2-
fluoro-1-tetralone in high yield, while in methanol the
yield of direct transformation was lower. N-fluorobenze-
nesulfonimide (AccufluorTM NFSi; 2), as a representative
of neutral N–F reagents, was found to be ineffective when
reaction was carried out in acetonitrile, while the metha-
nol mediated reaction resulted in formation in very high
yield of desired product. 1-(Chloromethyl)-4-fluoro-1,4-
Key words: fluorination, ketones, AccufluorTM NFTh, keto steroids
The versatile application of organofluorine compounds in
different branches of industry and medicine1 is generating
a comprehensive interest in and giving a strong impetus to
basic and applied research in their related chemistry.2 De-
velopment of new reagents and methods for site-selective
introduction of a fluorine atom into organic molecules un-
der mild reaction conditions has for a long time been the
main theme of such research. One of the most important
breakthroughs in these efforts has been accomplished by
the introduction and broad synthetic application of organ-
ic molecules incorporating a reactive N–F bond as mild
fluorinating reagents.3 N–F reagents, being easy handling
bench top materials usually with optimal stability/reactiv-
ity characteristics and attractive costs, have revolution-
ized the perception of synthesis of fluorinated organic
compounds. Fluorination of organic molecules, at least
when dealing with site-selective procedures, is no longer
the privilege of specialized laboratories with sophisticated
equipment and specially trained staff who must comply
with severe safety precautions. Manipulation of N–F re-
agents is an ordinary experimental protocol, convenient
for routine work in any organic chemistry laboratory.
One of the most beneficial changes resulting from bond-
ing of a fluorine atom to an organic molecule is often the
enhanced bioactivity of such a derivative in comparison to
its nonfluorinated analogue.1,4 On this basis fluorofunc-
tionalization of organic compounds bearing a carbonyl
group has been for a long time of special interest,1 since
this reactive functional site is often present in bioactive
molecules or in potential building blocks for their synthe-
diazoniabicyclo[2.2.2]octane
bis(tetrafluoro-borate)
(SelectfluorTM F-TEDA-BF4; 3) and its 1-fluoro-4-hy-
droxy substituted analogue AccufluorTM NFTh 4 are the
most representative materials of the N-fluoro bicyclic
amine salt class of N–F reagents. As evident from the data
in Table 1, NFTh seems to be the better reagent for direct
conversion of ketones to their -fluorinated derivatives.
Also, methanol is a better reaction medium for this pur-
pose than acetonitrile. The overall conclusion from this
Synthesis 2002, No. 17, Print: 02 12 2002.
Art Id.1437-210X,E;2002,0,17,2609,2615,ftx,en;C04802SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2610
S. Stavber et al.
SPECIAL TOPIC
trial experiment is that the NFTh/methanol combination
should be the best choice for the direct transformation of
a ketone to its -fluoro substituted derivative.
Table 1 Comparison of the Effect of N–F Reagents for Direct
-
Fluorination of Ketones
N–F reagent
Solvent
CH3CN
Yield (%)a
70
CH3OH
40
1
2
CH3CN
CH3OH
0
90
CH3CN
CH3OH
18
73
3
Scheme 1 Direct -fluorination of carbocyclic ketones. Reagents
and conditions: i Ketone (2 mmol), NFTh (2.1 mmol), MeOH (20
mL), reflux 0.5–3 h.
CH3CN
CH3OH
54
98
Aromatic ketones possessing a strongly activated aromat-
ic ring could be problematic substrates for the present re-
action knowing that behind the position to the keto
group, the aromatic ring is also an electron-rich part of the
molecule and thus sensitive to electrophilic reagents. On
the other hand, following our previous experience,8 the re-
gioselectivity of fluorofunctionalization of a variety of
such molecules could be regulated. 5-Methoxy-1-tetral-
one (15a, Table 2), known in the literature as valuable
starting material for many bioactive molecules and natural
products,10 was thus transformed to ( )-2-fluoro-5-meth-
oxy-3,4-dihydro-1(2H)-naphthalenone (16a), while its
hydroxy analogue 15b, likewise used as a valuable syn-
thon,11 or the five membered ring analogue 4-methoxy-1-
indanone (25a) also gave corresponding -fluoro deriva-
tives 16b or 26a effectively after using the NFTh/metha-
nol reaction protocol. In the same way, 2-fluoro
substituted derivatives of 1-indanone (18a) or 1-tetralone
(18b) bearing a dimethoxy functionalized aromatic ring
could be readily prepared from starting material 17. We
further checked the reactivity of some target molecules
which also include a potentially oxidizable functional
group or heteroatom as structural elements behind the
keto group. These kinds of molecules could also be prob-
lematic target materials for direct fluorofunctionalization
since N–F reagents are also known as strong oxidants.12
We chose two derivatives of thiophene i.e. 2-acetyl-
thiophene (19) and 6,7-dihydrobenzo[b]thiophen-4(5H)-
one (21) as targets and both were directly fluorinated to
the corresponding -fluoro derivatives 20 an 22 in high
4
a Determined from 19F NMR spectra of crude reaction mixture using
octafluoronaphthalene as internal standard.
Encouraged with this insight and previous related experi-
ence,7,8 we tried to apply the method to a comprehensive
range of keto functional groups containing organic mole-
cules, specially focusing on those which have been de-
clared as potentially bioactive compounds or have been
recognized as valuable synthons for more sophisticated
bioactive organic materials. The results of these efforts
are collected in the Scheme 1 and Table 2.
Ketones bearing a saturated carbocyclic ring as the struc-
tural element were transformed directly to their -fluoro
functionalized derivatives without any ring opening side
reactions being observed. Cyclododecanone (5a,
Scheme 1) and cyclopentadecanone (5b), known as the
fragrance material Exaltone,9 were selectively and almost
quantitatively transformed to -fluoro derivatives 6a–b,
as well as 4,4-dimethyl-cyclohex-2-en-1-one (7) to 6-
fluoro-4,4-dimethyl-cyclohex-2-en-1-one (8) and 3,3,5,5-
tetramethylcyclohexanone (9) to 2-fluoro-3,3,5,5-tetra-
methylcyclohexanone (10). 1-Fluorocyclohexyl phenyl
ketone (12) and 1-adamantyl fluoromethyl ketone (14)
were also readily obtained in high yield from the corre-
sponding ketones (11) and (13) following reaction with
NFTh in methanol.
Synthesis 2002, No. 17, 2609–2615 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Direct -Fluorination of Ketones
2611
Table 2 Direct -Fluorination of Ketones using AccufluorTM NFTh 4 in Methanola
Entry
Ketone
Time
Product
Yieldb (%)
1
2
a) 15 min
b) 30 min
a) 84
b) 77
15
16
3
4
a) 30 min
b) 5 min
a) 71
b) 78
18
20
17
19
5
6
5 h
71
82
1.2 h
22
24
21
23
7
70 min
79
8
9
a) 1 h
b) 1.5 h
a) 89
b) 81
26
25
10
11
1.5 h
1.5 h
78
72
27
29
28
30
a Reaction conditions: ketone (2 mmol), NFTh (2.1 mmol) b. Yields refer to the isolated pure products.
yield, while 2,3-dihydro-4H-1-benzopyranone (23) was signed on the basis of the coupling constants between the
transformed to its 3-fluoro derivative 24 and 7-methoxy- C-16 C-15 protons, the coupling constants between the
3(2H)-benzofuranone (25b) to its 2-fluoro derivative 26b. fluorine atom on the C-16 C-15 protons, and the NOESY
spectrum of the product. The proton on C-16 appeared as
Finally, we applied this methodology for direct fluorina-
a dd signal with the characteristic geminal F–H coupling
tion of ketones in the case of two keto steroids, namely
constant of 50.8 Hz and the H–H vicinal coupling constant
5 -cholestan-3-one (27) and 3 -hydroxy-5 -androstan-
17-one (29). Both could be directly fluorinated, using
NFTh in methanol. 5 -Cholestan-3-one (27) was readily
transformed to 2 -fluoro-5 -cholestan-3-one (28), show-
of 7.3 Hz. By modeling, the structure of the product 30 it
can be seen that in its most stable conformer when the C-
16 proton occupies an equatorial position, the dihedral an-
gle with the axial H-15 has a value around 20 degrees,
ing that one step in a recently reported methodology of
while the dihedral angle with the equatorial H-15 is
fluorination of cholesterol type steroids using 1-fluoro-
around 90 degrees. Following the Karplus rule, the cou-
pyridinium triflate as reagent and silyl enol ethers of the
pling constants should thus be as actually observed. The
target keto steroid as starting materials13 could be avoid-
signal for the fluorine atom, on the other hand, showed
ed. The fluorination of steroid 29 resulted regioselectively
in the formation of the 16-fluoro substituted product 30.
The stereochemistry of fluorine atom introduction was as-
ddd multiplicity with coupling constants of 50.8 Hz, 27.0
Hz, and 26.5 Hz which is also consistent with the model
assuming the fluorine atom occupies an axial position.
Synthesis 2002, No. 17, 2609–2615 ISSN 0039-7881 © Thieme Stuttgart · New York

2612
S. Stavber et al.
SPECIAL TOPIC
Direct Fluorination of Ketones; General Procedure
The stereochemistry on C-16 was also confirmed by the
appearance of an interaction on the NOESY spectrum be-
tween the C-16 proton and the C-13 methyl group, indi-
cating that they are on the same side of the plane. Hence
from all the mentioned arguments and observed spectro-
scopic data the product 30 was assigned as 16 -fluoro-3 -
hydroxy-5 -androstan-17-one. The assigned structure is
also reasonable from the mechanistic point of view con-
sidering the assumption that the enol tautomer is involved
in the fluorination process. In that case the -face of the
steroid 29 is sterically less accessible for the approach of
the reagent to the enol tautomer -bond because of the
ring junction -oriented methyl group.
To a soln of ketone (2 mmol) in MeOH (20 mL), AccufluorTM NFTh
(1.35 g, 2.1 mmol, of active compound) was added and the suspen-
sion heated under reflux until KI starch paper showed consumption
of the fluorinating reagent. The reaction solvent was removed under
reduced pressure, the crude reaction mixture dissolved in CH2Cl2
(50 mL), insoluble material filtered off, the soln washed with H2O
(50 mL), dried over Na2SO4 and the solvent evaporated. The isolat-
ed crude reaction mixtures were analyzed by 1H and 19F NMR. The
amounts of fluorinated products were determined from the 19F
NMR spectra of the crude reaction mixtures using octafluoronaph-
thalene as an additional standard and yields between 80 95% for -
fluoro carbonyl products were obtained. Since crude -fluoro car-
bonyl derivatives were in some cases (24, 26, 28 and 30) formed
partly in dimethylketal form, hydrolysis with 10% aq HCl soln in
MeCN was necessary. Pure solid products were obtained by crystal-
lization of crude -fluoro ketones while liquid products were puri-
fied by flash chromatography over SiO2 followed by distillation
under reduced pressure. The spectroscopic data of known com-
pounds 6a14 (83% from MeOH, mp 55 °C), 815(84% from pentane;
mp 65–66 °C), 1016 (84% from pentane; mp 33–34 °C), 1417 (75%
from pentane CH2Cl2; mp 80 °C), and 2813 (78% from pentane ac-
etone, mp 167–169 °C) were in agreement with reported data. New
compounds were fully characterized by NMR, MS, and IR spectros-
copy and their purity verified by combustion elemental analysis.
Considering our actual and some previously reported
experience7,8 1-fluoro-4-hydroxy-1,4-diazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate) (AccufluorTM NFTh)
seems to be a very convenient reagent for the direct fluo-
rofunctionalization of a broad structural range of ketones.
The reaction protocol involving NFTh as the fluorine
transfer reagent and methanol as the reaction medium
gave the optimal results regarding the regiospecificity of
fluorine atom introduction to the -keto position, even in
cases when other potentially active sites were present in
the target molecules. The presence of an activated aromat-
ic ring or an oxidizable heteroatom such as sulfur as the
structural element did not interfere with regiospecificity
of the fluorination, while in addition, regio- and stereose-
lective fluorofunctionalization of some keto steroids
could be achieved following the methodology described.
( )-2-Fluorocyclopentadecanone (6b)
Yield: 82%; white crystals; mp 53.5–55.5 °C (MeOH).
IR (KBr): 2930, 2857, 1721, 1460, 1366, 1063, 1019 cm–1.
1H NMR (60 MHz, CDCl3): = 1.3–2.0 [m, 24 H, (CH2)12], 2.3 (t,
JHH = 4 Hz, 2 H, CH2CO), 4.8 (dt, JFH = 51 Hz, JHH = 5 Hz, H2).
13C NMR (75 MHz, CDCl3): = 21.5 (d, JCF = 2.0 Hz), 22.3 (d,
JCF = 4.5 Hz), 26.1, 26.2, 26.3, 26.4, 26.5, 26.8, 27.3, 27.6, 31.7,
37.4, 42.1, 96.8 (d, JCF = 184.8 Hz, CFH), 208.5 (d, JCF = 16.2 Hz,
CO).
N-fluoro-2,6-dichloropyridinium tetrafluoroborate (FP-B800; 1)
and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoro-borate) (SelectfluorTM F-TEDA-BF4; 3) were pur-
chased from Apollo and used as received. N-Fluorobenzenesulfon-
imide (AccufluorTM NFSi; 2) and 1-fluoro-4-hydroxy-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (AccufluorTM
NFT H, 50% w/w on alumina; 4) were received as a gift from Allied
Signal and used as obtained. Starting materials in Table 1 were Sig-
ma-Aldrich samples and were used as received. Solvents (ACS
grade) were dried prior to use. Petroleum ether with a bp 40–60 °C
was used.
19F NMR (56.4 MHz, CDCl3): = –191.3 (ddd, JFH2 = 51 Hz, JFH3a
20 Hz, JFH3e = 19 Hz, F2).
MS (EI, 70 eV): m/z (%) = 242 (23) [M+], 166 (8), 139 (8), 125 (16),
111 (33), 98 (94), 84 (52), 69 (63), 55 (100).
Anal. calcd for C15H27FO: C, 74.33; H, 11.23. Found: C, 74.88; H,
11.78.
(1-Fluorocyclohexyl)(phenyl)methanone (12)
Yield: 71%, hygroscopic oily compound.
IR (neat): 1678, 1447, 1258, 1152, 1047, 965 cm–1.
1H NMR (60 MHz, CDCl3): = 1.7 [m, 8 H, (CH2)2], 2.1 (m, 2 H,
CH2), 7.4 (m, 3 H, ArH), 8.1 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): = 21.1 (d, JCF = 2.1 Hz, CH2), 24.8
(s, CH2), 33.2 (d, JCF = 22.6 Hz, CH2), 100.9 (d, JCF = 188.1 Hz,
CF), 128.3 (d, JCF = 1.1 Hz, ArCH), 129.9 (d, JCF = 8.2 Hz, ArCH),
132.9 (s, ArCH), 134.8 (d, JCF = 3.5 Hz, ArC), 201.4 (d JCF = 27.2
Hz, CO).
Melting points were determined on a Büchi 535 apparatus and are
uncorrected. 1H NMR spectra (except for pure products 28 and 30)
were recorded on a Varian EM360 L spectrometer at 60 MHz.
Chemical shifts are reported in ppm from TMS as the internal stan-
dard. 19F NMR spectra were recorded on a Varian EM360 L spec-
trometer at 56.4 MHz and chemical shifts are reported in ppm from
CCl3F as the internal standard. Data are reported as follows: chem-
ical shift, multiplicity, coupling constant, integration, and assign-
ment. 1H NMR spectra for compounds 28 and 30 were recorded on
a Varian Inova 300 spectrometer at 300 MHz and 13C NMR on the
same instrument at 75 MHz. Chemical shifts are reported in ppm
from TMS and data for 13C NMR are reported as follows: chemical
shift, multiplicity, coupling constant, assignment. NOESY NMR
were run with a mixing time of 0.2 s, relaxation delay of 3 s, and 4K
data points across F2. IR spectra were recorded on a Perkin-Elmer
1310 spectrometer. Standard KBr pellet procedures were used to
obtain IR spectra of solids, while a film of neat material was used to
obtain IR spectra of liquid products. Mass spectra were obtained on
an Autospec Q instrument under electron impact (EI) conditions at
70 eV. Elemental analyses were carried out on a Perkin-Elmer 2400
CHN analyzer.
19F NMR (56.4 M Hz, CDCl3): = –164.0 (m).
MS (EI, 70 eV): m/z (%) = 206 (10) [M+], 105 (100), 77 (30).
HRMS: m/z calcd for C13H15FO, 206.1110; found, 206.1107.
Anal. calcd for C13H15FO 1/4H2O: C, 74.08; H, 7.41. Found: C,
74.25; H, 7.36.
( )-2-Fluoro-5-methoxy-3,4-dihydro-1 (2H)-naphthalenone
(16a)
Yield: 84%, white crystals from pentane acetone, mp 123.8–
125.8 °C.
Synthesis 2002, No. 17, 2609–2615 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Direct -Fluorination of Ketones
2613
IR (KBr): 1693, 1598, 1579, 1474, 1443, 1348, 1263, 1119, 1095,
1032, 999, 940, 805, 754 cm–1.
( )-2-Fluoro-6,7-dimethoxy-3,4-dihydro-1-(2H)-naphthale-
none (18b)
Yield: 78%; white crystals from petroleum ether acetone; mp 163–
164.5 °C.
1H NMR (60 MHz, CDCl3): = 1.9–3.6 [m, 4 H, (CH2)2], 3.9 (s, 3
H, OCH3), 5.2 (ddd, JHF = 50, 12, 6 Hz, 1 H, H2), 7.2 (d, JHH = 8 Hz,
1 H, H8), 7.4 (dd, JHH = 8, 8 Hz, 1 H, H7), 7.8 (d, J = 8 Hz, 1 H, H6).
13C NMR (75 MHz, CDCl3): = 21.0 (d, JCF = 11.7 Hz, C4), 29.2
(d, JCF = 19.5 Hz, C3), 55.7 (s, OCH3), 91.1 (d, JCF = 191.6 Hz, C2),
114.9 (s, ArCH), 119.1 (s, ArCH), 126.7 (s, ArC), 127.8 (s, ArCH),
131.9 and 132.3 (d, JCF = 2.0 Hz, ArC), 156.7 (s, ArC), 193.7 (d,
IR (KBr): 1677, 1600, 1510, 1470, 1453, 1417, 1374, 1338, 1269,
1238, 1224, 1203, 1148, 1073, 1046, 1017, 972, 933, 884, 867, 809,
770 cm–1.
1H NMR (60 MHz, CDCl3): = 2.5 (m, 2 H, H4), 3.1 (m, 2 H, H3),
4.0 (s, 6 H, OCH3), 5.2 (ddd, J = 49, 12, 6 Hz, 1 H, H2), 6.8 (s, 1 H,
ArH), 7.6 (s, 1 H, ArH).
JCF = 14.9 Hz, CO).
19F NMR (56.4 MHz, CDCl3): = –191.5 (md, JFH = 50 Hz).
MS (EI, 70 eV): m/z (%) = 194 (100) [M+], 148 (91), 120 (74), 105
13C NMR (75 MHz, CDCl3): = 26.7 (d, JCF = 12.3 Hz, C4), 30.4
(d, JCF = 19.4 Hz, C3), 56.0 (s, OCH3), 56.1 (s, OCH3), 90.9 (d,
JCF = 189.6 Hz, C2), 108.5 (d, JCF = 2.0 Hz, ArCH), 110.1 (s,
ArCH), 124.2 (s, ArC), 138.2 (d, J = 1.5 Hz, ArC), 148.3 (s, ArC),
154.2 (s, ArC), 192.1 (d, JCF = 14.9 Hz, CO).
(30), 90 (77), 77 (39).
Anal. calcd for C11H11FO2: C, 68.03; H, 5.71. Found: C, 68.49; H,
5.75.
19F NMR (56.4 MHz, CDCl3): = –191.0 (td, JFH = 49, 9.5 Hz, F2).
( )-2-Fluoro-5-hydroxy-3,4-dihydro-1 (2H)-naphthalenone
MS (EI, 70 eV): m/z (%) = 224 (88 ) [M+], 178 (75), 150 (100), 135
(16b)
(18), 107 (17), 77 (15).
Yield: 77%; white crystals from CHCl3 CH3CN; mp198.8–
200.7 °C.
Anal. calcd for C12H13FO3: C, 64.28; H, 5.84. Found: C, 64.70; H,
6.07.
IR (KBr): 1670, 1595, 1580,1471, 1330, 1280, 1222, 1110, 1091,
1042, 1007, 967, 912, 852, 811, 796, 708, 753 cm–1.
2-Fluoro-1-(2-thienyl)ethanone (20)
Yield: 71%; white crystals from pentane acetone; mp 51.3–
54.4 °C.
1H NMR (300 MHz, CD3CN): = 2.20 (m, 1 H, H3a), 2.50 (m, 1 H,
H3e), 2.8 (m, 1 H, H4a), 3.15 (md, JHH = 13.0 Hz, 1 H, H4e), 5.23
(ddd, JHF = 50 Hz, JHH = 12, 6 Hz, 1 H, H2), 7.07 (d, JHH = 7.8 Hz,
1 H, H8), 7.22 (dd, JHH = 8.0, 7.8 Hz, 1 H, H7), 7.43 (s, 1 H, OH),
7.48 (d, JHH = 8 Hz, 1 H, H6).
13C NMR (75 MHz, CD3CN): = 21.8 (d, JCF = 12.8 Hz, C4), 30.1
(d, JCF = 18.7 Hz, C3), 92.4 (d, JCF = 184.8 Hz, C2), 118.4 (s,
ArCH), 119.3 (s, ArC), 120.8 (s, ArCH) 128.7 (s, ArCH), 131.4 and
133.8 (d, JCF = 1.6 Hz, ArCH), 155.3 (s, ArC), 194.9 (d, JCF = 14.4
Hz, CO).
IR (KBr): 1675, 1416, 1255, 1100, 1087, 1053, 922, 857, 775, 750
cm–1.
1H NMR (60 MHz, CDCl3): = 5.4 (d, JHF = 49 Hz, 2 H, CH2F), 7.3
(dd, JHH = 5, 5 Hz, 1 H, H3), 7.9 (dd, JHH = 5, 2 Hz, 1 H, H4), 8.0
(dd, JHH = 5, 2 Hz, 1 H, H5).
13C NMR (75 MHz, CDCl3): = 83.8 (d, JCF = 188.1 Hz, CH2F),
128.5 (d, JCF = 1.5 Hz), 133.2 (d, JCF = 6.2 Hz), 135.0 (d, JCF = 1.0
Hz), 139.9 (d, JCF = 2.5 Hz), 187.2 (d, JCF = 18.0 Hz, CO).
19F NMR (56.4 MHz, CDCl3): = –226.7 (t, JFH = 49 Hz, FCH2).
MS (EI, 70 eV): m/z (%) = 144 (19) [M+], 111 (100), 83 (15).
19F NMR (56.4 M Hz, CD3CN): = –190.7 (md, JFH = 50 Hz, F2).
MS (EI, 70 eV): m/z (%) = 180 (80), [M+], 134 (100), 106 (76), 78
(34).
Anal. calcd for C6H5FOS: C, 49.99; H, 3.50. Found: C, 49.72; H,
3.49.
Anal. calcd for C10H9FO2: C, 66.66; H, 5.03. Found: C, 66.85; H,
5.16.
( )-5-Fluoro-6,7-dihydrobenzo[b]thiophen-4 (5H)-one (22)
Yield: 82%; white crystals from pentane CH2Cl2; mp 52.1–
53.3 °C.
( )-2-Fluoro-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (18a)
Yield: 71%; white crystals from petroleum ether acetone; mp 128–
130 °C.
IR (KBr): 1680, 1520, 1414, 1356, 1254, 1215, 1120, 1082, 1032,
989, 918, 845, 735, 648 cm–1.
1H NMR (60 MHz, CDCl3): = 2.6 (m, 2 H, H7), 3.2 (m, 2 H, H6),
5.2 (ddd, JHF = 49 Hz, JHH 9.5, 6 Hz, 1 H, H5), 7.2 (d, JHH = 6 Hz, 1
H, H3), 7.5 (d, JHH = 6 Hz, 1 H, H2).
13C NMR (75 MHz, CDCl3): = 23.1 (d, JCF = 11.1 Hz, C7), 31.0
(d, JCF = 20.1 Hz, C6), 90.5 (d, JCF = 185.9 Hz, C5), 125.0 (s), 125.1
(s), 136.0 (d, JCF = 1.0 Hz), 155.0 (d, JCF = 1.6 Hz), 187.7 (d,
JCF = 16.1 Hz, CO).
IR (KBr): 1707, 1599, 1583, 1497, 1341, 1304, 1265, 1209, 1119,
1050, 1001, 859, 842, 774 cm–1.
1H NMR (60 MHz, CDCl3): = 3.1–3.8 (m, 2 H, H3), 4.0 (s, 3 H,
OCH3), 4.1 (s, 3 H, OCH3), 5.3 (ddd, JHF = 51 Hz, JHH = 6, 4 Hz, 1
H, H2), 7.0 (s, 1 H, ArH), 7.3 (s, 1 H, ArH).
13C NMR (75 MHz, CDCl3): = 33.2 (d, JCF = 22.0 Hz, C3), 56.1
(s, OCH3), 56.4 (s, OCH3), 90.6 (d, JCF = 192.1 Hz, C2), 104.8 (s,
ArCH), 107.6 (s, ArCH), 126.7 (d, JCF = 2.1 Hz, ArC), 145.6 (d,
J = 6.2 Hz, ArC), 150.1 (s, ArC), 156.9 (s, ArC), 198.4 (d,
JCF = 15.3 Hz, CO).
19F NMR (56.4 M Hz, CDCl3): = –161.2 (td, JFH = 49, 9.4 Hz, F5).
MS (EI, 70 eV): m/z (%) = 170 (76) [M+], 124 (100), 96 (89), 70
19F NMR (56.4 MHz, CDCl3): = –193.2 (ddd, JFH = 51, 21, 9 Hz,
F2).
(25).
MS (EI, 70 eV): m/z (%) = 210 (100) [M+], 195 (31), 167 (18), 139
(24), 91 (43).
Anal. calcd for C8H7FOS: C, 56.45; H, 4.15. Found: C, 56.29; H,
4.22.
Anal. calcd for C11H11FO3: C, 62.85; H, 5.27. Found: C, 63.14; H,
5.40.
( )-3-Fluoro-2,3-dihydro-4H-1-benzopyranone (24)
Yield: 79%; white crystals from pentane–acetone; mp 66.5–
67.3 °C.
IR (KBr): 1709, 1607, 1575, 1524, 1452, 1283, 1237, 1212, 1146,
1127, 1094, 1036, 1013, 944, 834, 757, 650 cm–1.
Synthesis 2002, No. 17, 2609–2615 ISSN 0039-7881 © Thieme Stuttgart · New York

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S. Stavber et al.
SPECIAL TOPIC
1H NMR (60 MHz, CDCl3): = 4.6 (m, 2 H, H2), 5.1 (ddd, JHF = 48
Hz, JHH 8, 5 Hz, 1 H, H3), 7.1 (dd, JHH = 8, 8 Hz, 2 H, H6,H7), 7.5
(dd, JHH = 8, 3 Hz, 1 H, H5), 7.9 (dd, J = 8, 3 Hz, 1 H, H8).
13C NMR (75 MHz, CDCl3): = 12.29, 14.06, 20.10, 28.26, 29.79
(d, JCF = 20.4 Hz, C15), 30.60, 31.32, 34.87, 35.66, 36.86, 38.00,
44.76, 47.82, 48.38, 51.46, 54.25, 71.03 (s, C3), 90.17 (d,
J
CF = 183.45 Hz, C16), 213.49 (d, FCF = 20.4 Hz, CO).
19F NMR (56.4 MHz, CDCl3); = –192.7 (ddd, JFH16 = 50.8 Hz,
FH15 = 27.0, 26.5 Hz, F16).
13C NMR (75 MHz, CDCl3): = 68.7 (d, JCF = 26.2 Hz, C2), 85.6
(d, JCF = 188.0 Hz, C3), 117.9 (s, ArCH), 119.4 (s, ArC) 122.3 (s,
ArCH), 127.7 (s, ArCH), 136.8 (s, ArCH), 161.2 (s, ArC), 187.0 (d,
J
J
CF = 16.1 Hz, CO).
MS (EI, 70 eV): m/z (%) = 308 (26) [M+], 235 (16), 234 (81), 219
(15), 216 (52), 201 (22), 190 (33), 124 (25), 109 (28), 108 (100),
107 (62), 97 (22), 95 (28), 93 (30), 83 (30), 81 (36), 71 (28), 69 (48),
67 (25), 57 (54), 55 (52).
19F NMR (56.4 MHz, CDCl3): = –203.3 (ddd, JFH = 48, 14, 12 Hz,
F3).
MS (EI, 70 eV): m/z (%) = 166 (50) [M+], 136 (8), 120 (100), 92
(68), 77 (34).
Anal. calcd for C19H29FO2: C, 73.99; H, 9.48. Found: C, 73.66; H,
9.70.
Anal. calcd for C9H7FO2: C, 65.06; H, 4.25. Found: C, 65.09; H,
4.26.
Acknowledgements
( )-2-Fluoro-4-methoxy-2,3-dihydro-1H-inden-1-one (26a)
Yield: 89%; white crystals from petroleum ether acetone;
mp 106.5–108.4 °C.
The authors are grateful to Dr. J. Plavec for 13C NMR spectra, T. Sti-
panovic and Prof. B. Stanovnik for elemental combustion analysis,
and to the Ministry of Education, Science and Sport of the Republic
of Slovenia for financial support.
IR (KBr): 1720, 1592, 1487, 1433, 1267, 1082, 1062, 992, 937, 849,
800, 761 cm–1.
1H NMR (60 MHz, CDCl3): = 3.0–3.8 (m, 2 H, H3), 3.9 (s, 3 H,
OCH3), 5.2 (ddd, JHF = 51 Hz, JHH = 7, 5 Hz, 1 H, H2), 7.1–7.5 (m,
3 H, ArH).
13C NMR (75 MHz, CDCl3): = 30.0 (d, JCF = 22.6 Hz, C3), 55.6
(s, OCH3), 90.5 (d, JCF = 193.2 Hz, C2), 116.0 (s, ArCH), 116.5 (s,
ArCH), 129.9 (s, ArCH), 135.1 (d, JCF = 1.1 Hz, C8), 138.7 (d,
J = 6.2 Hz, C9), 156.9 (d, JCF = 1.5 Hz, C4), 200.2 (d, JCF = 15.4
Hz, CO).
References
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Hz, F2).
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(36), 109 (43).
Anal. calcd for C10H9FO2: C, 66.66; H, 5.03. Found: C, 67.09; H,
5.01.
( )-2-Fluoro-7-methoxy-3-(2H)-benzofuranone (26b)
Yield: 81%; yellow crystals from pentane CH2Cl2; mp 61–63 °C.
IR (KBr): 1743, 1601, 1508, 1440, 1321, 1279, 1170, 1100, 1070,
1036, 998, 919, 832, 760 cm–1.
1H NMR (60 MHz, CDCl3): = 4.0 (s, 3 H, OCH3), 5.9 (d, JHF = 59
Hz, 1 H. H2), 7.3 (m, 3 H, ArH).
13C NMR (75 MHz, CDCl3):
CF = 238.8 Hz, C2), 116.3 (s, ArCH) 119.5 (s, C8), 120.9 (s,
= 56.5 (s, OCH3), 103.2 (d,
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Chem. 1995, 60, 4730. (c) Davis, F. A.; Zhou, P.; Murphy,
C. K.; Sundarababu, G.; Qi, H.; H’an, W.; Przeslawski, R.
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ArCH), 124.4 (s, ArCH), 146.2 (s, C9), 161.1 (s, C7), 193.1 (d,
JCF = 14.5 Hz, CO).
19F NMR (56.4 MHz, CDCl3); = –140.2 (d, JFH = 59 Hz, F2).
MS (EI, 70 eV): m/z (%) = 182 (98) [M+], 164 (22), 153 (35), 133
(36), 104 (52), 91 (14), 76 (100).
Anal. calcd for C9H7FO3: C, 59.35; H, 3.87. Found: C, 59.19; H,
4.00.
16 -Fluoro-3 -hydroxy-5 -androstan-17-one (30)
Yield: 72%; white crystals from pentane acetone; mp 160–162 °C.
IR (KBr): 1742, 1446, 1369, 1299, 1072, 1041, 1003, 918, 869, 847
cm–1.
1H NMR (300 MHz, CDCl3): = 0.7–2.2 (m, 20H), 0.83 (s, 3 H,
CH3C19), 0.91 (s, 3 H, CH3C18), 3.58 (m, 1 H, H3), 5.08 (dd,
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Berlin, 1994.
Synthesis 2002, No. 17, 2609–2615 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Direct -Fluorination of Ketones
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Synthesis 2002, No. 17, 2609–2615 ISSN 0039-7881 © Thieme Stuttgart · New York