Fluorination of ketones using iodotoluene difluoride

Article abstract of DOI:10.1055/s-2005-872105

Fluorination of ketones was achieved by the reaction of silyl enol ethers with iodotoluene difluoride in the presence of BF₃·OEt ₂ and a Et₃N·HF complex. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872105

2
602
PAPER
Fluorination of Ketones Using Iodotoluene Difluoride
F
S
luorination o
a
Ketone
s
U
e
sing Iodoto
k
luene
D
ifluo
o
ride Sato, Masanori Yoshida, Shoji Hara*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066556; E-mail: hara@org-mc.eng.hokudai.ac.jp
Received 24 December 2004
rination of 2a (Table 1). Though 1a was consumed at
78 °C in the presence of BF ·OEt , the addition of metal
fluorides such as KF and CsF, which are only slightly sol-
uble in an organic solvent, failed to improve the yields of
Abstract: Fluorination of ketones was achieved by the reaction of
silyl enol ethers with iodotoluene difluoride in the presence of
BF ·OEt and a Et N·HF complex.
–
3
2
3
2
3
Key words: fluorination, iodotoluene difluoride, silyl enol ether,
ketone, hypervalent iodine
3
a. On the other hand, the addition of Et N·HF complexes
3
(
cially available Et N·3HF
Et N·nHF) could improve the results. When a commer-
3
1
4,15
was used as the fluoride
source, 3a could be obtained in 71% yield together with a
3
Introduction of a fluorine atom into the a-position of car-
bonyl compounds is the most effective method for the
synthesis of a-fluorinated carbonyl compounds which
have been used as important synthons in the preparation
small amount of 4a (9%) and 5a (4%). Et N·2HF could
3
slightly improve the result but Et N·HF, TBAF, and
3
Et NF were less effective than Et N·2HF or Et N·3HF.
4
3
3
1
,2
of more complex fluorine compounds. Though electro-
philic fluorination reagents such as N-fluoro reagents
IF2
1
) BF3⋅OEt2
O
BF4
ITol-p
3
have been used for their synthesis, dangerous F is neces-
2
CH Cl2 –78 °C
F source
2
sary for their preparation, and such reagents are expensive
even if they are commercially available. Recently we re-
ported that the direct fluorination of b-dicarbonyl com-
pounds can be achieved using iodotoluene difluoride
OSiMe3
Ph
O
2
)
2
a
CH3
Ph
1a
ITDF
O
O
4
,5
O
(
F . However, application of ITDF is restricted to b-di-
ITDF) which can be prepared in large quantity without
,7
Ph
F
OH
+
6
+
+
Ph
Ph
Ph
2
Ph
4
,5
carbonyl compounds or a-sulfanylated carbonyl com-
3a
5a
O
4
a
8
–11
pounds,
and ITDF is inert to monocarbonyl
Scheme 1
compounds. Previously, Tsushima et al. applied ITDF for
the reaction with silyl enol ethers of steroidal ketones for
1
2
Under the conditions, silyl enol ethers of various acyclic
and cyclic ketones could be converted to the correspond-
ing a-fluoroketones 3 (Table 2). Introduction of a fluorine
atom to methyl (entry 4), methylene (entries 1,2,5–9), and
even methine carbon (entry 3) was also possible. When
the synthesis of steroidal fluoroketones. However, ole-
finic by-products were competitively formed and yields of
the desired a-fluoro ketones were low. During our contin-
uous study of fluorination of carbonyl compounds using
ITDF, we succeeded in improving the yield of fluorinated
carbonyl compounds in the reaction of ITDF with silyl
enol ethers.
a
Table 1 Effect of Fluoride Source on the Fluorination of 1a
When a silyl enol ether of acetophenone 1a was allowed
to react with ITDF at room temperature, it took three
hours until the complete consumption of 1a, and ace-
tophenone and its dimer 5a were obtained as main prod-
ucts. Under the conditions, the formation of an iodonium
salt 2a, which must be a key intermediate for the fluorinat-
b
Fluoride Source
Yield (%)
3
a
4a
9
5a
4
Et N·3HF
3
71
73
40
25
1
Et N·2HF
3
7
4
1
2
ed product 3a, seems to be slow and the generated iodo-
nium salt 2a decomposed to acetophenone or reacted with
the remaining 1a to give 5a (Scheme 1). Zhadnkin et al.
reported that the iodonium salts can be stably prepared at
lower temperature by the reaction of 1 with an iodoarene
Et N·HF
3
–
10
3
TBAF
9
Et NF
4
49
80
75
8
1
3
difluoride-BF ·OEt complex. In order to obtain 2a at
3
2
c
CsF
–
4
low temperature, BF ·OEt was used with ITDF, and var-
3
2
c
ious fluoride sources were applied to accelerate the fluo- KF
10
5
a
Unless otherwise mentioned, CH Cl was used as solvent.
2
2
SYNTHESIS 2005, No. 15, pp 2602–2605
x
x.
x
x
.
2
0
0
5
b
c
NMR yield based on 1a.
MeCN was used as solvent.
Advanced online publication: 29.07.2005
DOI: 10.1055/s-2005-872105; Art ID: F18704SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Fluorination of Ketones Using Iodotoluene Difluoride
2603
a
Table 2 Reaction of Silyl Enol Ethers 1 with ITDF
cholestan-3-one 6 was treated with ITDF, the b-isomer of
-fluorocholestan-3-one (7-b) was obtained as a main
2
b
Entry Silyl Enol Ether 1
Product 3
Yield (%)
product (Scheme 2). This unusual stereoselectivity can be
explained by the formation of the iodonium intermedi-
O
OSiMe3
1
2
ate. ITDF attacks 6 from the less hindered a-face to give
the a-isomer of the iodonium intermediate which reacts
with a fluoride ion with inversion of stereochemistry to
1
60
Ph
Ph
3b
1b
F
19
O
give the 7-b.
OSiMe3
C5H11
2
C H
5
82
11
Ph
Ph
Ph
Ph
3
c
1
c
F
F
OSiMe3
O
3
4
5
66
70
85
H
IDTF, BF3⋅OEt2
1d
3d
H
H
Et3N⋅2HF, CH2Cl2
Me3SiO
OSiMe3
O
H
F
6
C10H21
C6H13
C10H21
C6H13
1e
3e
F
F
O
+
OSiMe3
C5H11
C H
5
11
O
O
H
H
1f
3f
F
8
2%
7-α
38 : 62
7-β
OSiMe3
O
F
Scheme 2
6
62
1
g
3g
The IR spectra were recorded using a JASCO FT/IR-410 spectrom-
1
19
13
eter. The H NMR (400 MHz), F NMR (376 MHz), and C NMR
100 MHz) spectra were recorded in CDCl on a JEOL JNM-A400II
OSiMe3
O
(
FT NMR and the chemical shifts, d are referred to TMS ( H, C)
3
F
1
13
7
8
60
50
1
and CFCl ( F), respectively. The EI high-resolution mass spectra
9
3
were measured on a JEOL JMS-700TZ, JMS-FABmate or JMS-
HX110 spectrometer. Melting points are measured by Yanagimoto
micro melting point apparatus and are uncorrected.
1
h
3h
OSiMe3
O
7
ITDF was prepared from iodotoluene as reported previously.
BF ·OEt and Et N·3HF were purchased from Tokyo Kasei Co.,
F
3
2
3
1i
3i
Ltd., and distilled under N before use. Et N·2HF and Et N·HF were
2 3 3
prepared by the addition of freshly distilled Et N to Et N·3HF. The
3
3
OSiMe3
O
F
silyl enol esters 1 were prepared from the corresponding ketones ac-
c
9
61
20
cording to the literature. Ketones were obtained from Tokyo Kasei
Co., Ltd., and used without purification.
But
But
1j
3j
a
Fluorination of Ketones 1 with Iodotoluene Difluoride; General
Procedure
To a CH Cl solution (10 mL) of ITDF (256 mg, 1.0 mmol) in Te-
The reactions were carried out in CH Cl using ITDF, BF ·OEt , and
3
2
2
2
Et N·2HF to 1.
3
b
Isolated yields based on 1 and yields of olefinic by-products were
less than 5%.
2
2
2
1
flon FEP vessel were added at –78 °C, BF ·OEt (142 mg, 1.0
3
2
c
mmol), and after 10 min, silyl enol ether 1 (1.0 mmol). The reaction
mixture was stirred at –78 °C for 2 h and a CH Cl solution (5 mL)
Ratio of cis:trans = 1:1.
2
2
of Et N·2HF (706 mg, 5.0 mmol) was added. After 1 h, the mixture
3
was poured into H O and the separated aqueous layer was extracted
2
cyclic ketone silyl enol ethers were used (entries 6–9), the with CH Cl (2 × 10 mL). The combined organic layers were dried
2 2
(
MgSO ) and product 3 was obtained by column chromatography
formation of an olefinic by-product was observed to an
extent of <5%.
4
(silica gel, hexane–Et O).
2
Fluorinated analogs of steroids have been of great interest 2-Fluoroacetophenone (3a)
for the study of their metabolic mechanism, and 2-fluoro- IR (neat): 2992, 1700, 1598, 1450, 1233, 1132 cm .
–
1
1
cholesterols were synthesized from their enol esters by the
H NMR: d = 5.55 (d, JH,F = 46.8 Hz, 2 H), 7.26–7.53 (m, 2 H),
reaction with electrophilic fluorinating regents. However, 7.62–7.66 (m, 1 H), 7.89–7.94 (m, 2 H).
the products obtained by these methods are always a-iso-
mers which are more favorable both kinetically and ther- J = 47 Hz)].
19
22
F NMR: d = –231.4 (t, JH,F = 46.8 Hz, 1 F) [(Lit. d = –230.3 (t,
modynamically, and it was difficult to synthesize the b-
1
6–18
2-Fluoro-1-phenylpropan-1-one (3b)
IR (neat): 2955, 2932, 2860, 1699, 1597, 1449 cm .
isomers.
On the other hand, when silyl enol ether of
–
1
Synthesis 2005, No. 15, 2602–2605 © Thieme Stuttgart · New York

2
604
S. Sato et al.
PAPER
1
H NMR: d = 1.64 (dm, JH,F = 38.6 Hz, 3 H), 5.70 (dq, JH,F = 48.8
Hz, JH,H = 5.6 Hz, 1 H), 7.48–7.52 (m, 2 H), 7.60–7.64 (m, 1 H),
2-Fluoroindan-1-one (3i)
White solid; mp 56–58 °C (Lit. mp 54–56 °C)
2
3
7
.96–7.99 (m, 2 H).
–1
IR (KBr): 2924, 1719, 1607, 1465, 1087 cm .
1
9
22
F NMR: d = –181.95 to –182.27 (m, 1 F) (lit. d = –180.5).
1
H NMR: d = 3.19–3.30 (m, 1 H), 3.60–3.68 (m, 1 H), 5.27 (dm,
JH,F = 51.0 Hz, 1 H), 7.43–7.48 (m, 2 H), 7.66–7.70 (m, 1 H), 7.81
2-Fluoro-1-phenylheptan-1-one (3c)
IR (neat): 2955, 2932, 2860, 1699, 1597, 1449 cm .
(
d, J = 7.6 Hz, 1 H).
–
1
1
9
23
F NMR: d = –194.17 (ddd, JH,F = 51.0, 23.2, 7.4 Hz, 1 F) [(Lit.
d = –192.5 (ddd, JH,F = 50, 22.5, 9 Hz)].
1
H NMR: d = 0.89 (t, JH,H = 7.3 Hz, 3 H), 1.30–1.38 (m, 4 H), 1.50–
1
7
.57 (m, 2 H), 1.90–2.02 (m, 2 H), 5.57 (dm, JH,F = 49.5 Hz, 1 H),
.47–7.97 (m, 5 H).
cis-2-Fluoro-4-tert-butylcyclohexanone (cis-3j)
16
White solid; mp 37 °C (Lit. mp 40 °C).
1
3
C NMR: d = 14.01, 22.47, 24.54 (d, JC,F = 3.3 Hz), 31.41, 32.83
d, JC,F = 20.7 Hz), 93.97 (d, JC,F = 182.8 Hz), 128.80 (2 C), 128.91
d, JC,F = 3.3 Hz), 133.78 (2 C), 134.42, 197.03 (d, JC,F = 19.8 Hz).
(
(
1
–1
IR (KBr): 2962, 1737, 1368 cm .
1
H NMR: d = 0.95 (s, 9 H), 1.39–1.50 (m, 1 H), 1.54–1.69 (m, 2 H),
2.07–2.18 (m, 1 H), 2.28–2.37 (m, 1 H), 2.49–2.56 (m, 2 H), 4.93
(dm, JH,F = 48.5 Hz, 1 H).
9
F NMR: d = –190.54 to –190.27 (m, 1 F).
HRMS (EI): m/z calcd for C H FO: 208.1250; found: 208.1257.
1
3
17
1
9
F NMR: d = –188.62 (dm, JH,F = 48.2 Hz, 1 F).
2
IR (neat): 2988, 1685, 1179 cm .
-Fluoro-2-methyl-1-phenylpropan-1-one (3d)
–
1
trans-2-Fluoro-4-tert-butylcyclohexanone (trans-3j)
16
White solid; mp 69–71 °C (Lit. mp 74 °C).
1
H NMR: d = 1.70 (d, JH,F = 21.5 Hz, 6 H), 7.44–7.48 (m, 2 H),
.55–7.58 (m, 1 H), 8.06–8.08 (m, 2 H).
7
–1
IR (KBr): 2956, 2871, 1722, 1365 cm .
1
9
22
F NMR: d = –144.32 to –143.98 (m, 1 F) (Lit. d = –142.1).
1
H NMR: d = 0.92 (s, 9 H), 1.42–1.70 (m, 2 H), 1.84–1.92 (m, 1 H),
2
(
.10–2.19 (m, 1 H), 2.35–2.45 (m, 2 H), 2.76–2.86 (m, 1 H), 4.67
dm, JH,F = 46.8 Hz, 1 H).
1-Fluorododecan-2-one (3e)
IR (neat): 2925, 2855, 1728, 1465, 1047 cm .
–
1
1
9
F NMR: d = –186.28 to –185.98 (m, 1 F).
1
H NMR: d = 0.88 (t, JH,F = 7.0 Hz, 3 H), 1.26–1.30 (m, 14 H),
1
(
.56–1.65 (m, 2 H), 2.54 (td, JH,H = 7.4 Hz, JH,F = 2.9 Hz, 2 H), 4.80
d, JH,F = 47.8 Hz, 2 H).
2a-Fluorocholestan-3-one (7-a)
White solid; mp 161–163 °C (Lit. mp 168–169 °C).
17
1
3
C NMR: d = 14.12, 22.69, 22.76, 29.15, 29.31, 29.35, 29.45,
9.55, 31.90, 38.31, 84.97 (d, JC,F = 184.4 Hz), 207.29 (d,
–1
IR (KBr): 2939, 2865, 1735, 1467, 1382 cm .
2
JC,F = 19.0 Hz).
1
H NMR: d = 0.85–2.03 (m, 41 H), 2.21–2.53 (m, 3 H), 4.98 (dm,
JH,F = 48.1 Hz, 1 H).
1
9
F NMR: d = –228.01 (t, JH,F = 47.8 Hz, 1 F).
1
9
17
F NMR: d = –194.67 (dm, JH,F = 48.1 Hz, 1 F) (Lit. d =
194.48).
HRMS (EI): m/z calcd for C H FO: 202.1741; found: 202.1737.
1
2
23
–
6-Fluorotridecan-7-one (3f)
IR (neat): 2956, 2932, 1699, 1597, 1449 cm .
2b-Fluorocholestan-3-one (7-b)
White solid; mp 85–87 °C.
–
1
1
H NMR: d = 0.87–0.91 (m, 6 H), 1.28–1.37 (m, 10 H), 1.40–1.48
(m, 2 H), 1.54–1.61 (m, 2 H), 1.70–1.86 (m, 2 H), 2.53–2.64 (m, 2
H), 4.71 (dm, JH,F = 50.4 Hz, 1 H).
–1
IR (KBr): 2932, 2861, 1735, 1467, 1382 cm .
1
H NMR: d = 0.85–1.87 (m, 40 H), 1.97–2.02 (m, 1 H), 2.16–2.26
m, 2 H), 2.59–2.68 (m, 1 H), 4.79 (dt, JH,F = 49.8 Hz, JH,H = 4.6 Hz,
(
1
3
C NMR: d = 13.97, 14.03, 22.44 (d, JC,F = 10.8 Hz), 22.64, 24.21
d, JC,F = 2.5 Hz), 28.84, 31.34, 31.58, 31.93, 32.14, 38.04, 96.09 (d,
JC,F = 183.6 Hz), 210.54 (d, JC,F = 24.8 Hz).
1
H).
(
1
3
C NMR: d = 12.03, 13.82, 13.86, 18.64, 21.51, 22.55, 22.80,
3.80, 24.14, 27.99, 28.19, 28.64, 31.47, 34.91, 35.74, 35.99, 36.11,
9.48, 39.81, 41.69, 44.90 (d, JC,F = 19.0 Hz), 45.84, 54.68, 56.10,
2
3
1
9
F NMR: d = –192.64 to –192.35 (m, 1 F).
HRMS (EI): m/z calcd for C H FO: 216.1890; found: 216.1890.
56.21, 92.33 (d, JC,F = 180.3 Hz), 206.90 (d, JC,F = 18.2 Hz).
1
3
25
1
9
F NMR: d = –183.72 to –184.00 (m, 1 F).
6
IR (neat): 2943, 1696, 1599, 1449 cm .
-Fluoro-6,7,8,9-tetrahydro5H-benzo[a]cyclohepten-5-one (3g)
–
1
HRMS (EI): m/z calcd for C H FO: 404.3454; found: 404.3453.
27 45
1
H NMR: d = 1.89–2.19 (m, 3 H), 2.29–2.43 (m, 1 H), 2.92–3.08
m, 2 H), 5.24 (dm, JH,F = 48.8 Hz, 1 H), 7.22–7.26 (m, 1 H), 7.31–
(
References
7
.35 (m, 1 H), 7.42–7.46 (m, 1 H), 7.77 (d, JH,F = 7.8 Hz, 1 H).
(
(
1) Rozen, S.; Filler, R. Tetrahedron 1985, 41, 1111.
2) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991.
3) For a review article on electrophilic fluorination, see:
Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55,
12431.
1
9
23
F NMR: d = –183.3 to –183.15 (m, 1 F) (Lit. d = –183).
2-Fluoro-1-tetralone (3h)
White solid; mp 34 °C (Lit. mp 38–40 °C).
(
2
3
–
IR (KBr): 2938, 2898, 1707, 1602, 1271, 1227 cm .
1
1
(4) Hara, S.; Sekiguchi, M.; Ohmori, A.; Fukuhara, T.; Yoneda,
N. Chem. Commun. 1996, 1899.
H NMR: d = 2.31–2.43 (m, 1 H), 2.55–2.63 (m, 1 H), 3.13–3.16
m, 2 H), 5.14 (dm, JH,F = 48.1 Hz, 1 H), 7.26–7.55 (m, 3 H), 8.08
d, JH,F = 7.8 Hz, 1 H).
(
(
1
(
5) Yoshida, M.; Fujikawa, K.; Sato, S.; Hara, S. Arkivoc 2003,
vi, 36; www.arkat-usa.org.
(6) Carpenter, W. J. Org. Chem. 1966, 31, 2688.
9
23
F NMR: d = –190.99 (dm, JH,F = 48.2, 1 F) [(Lit. d = –192 (dm,
JH,F = 47.5 Hz)].
(7) Sawaguchi, M.; Ayuba, S.; Hara, S. Synthesis 2002, 1802.
Synthesis 2005, No. 15, 2602–2605 © Thieme Stuttgart · New York

PAPER
Fluorination of Ketones Using Iodotoluene Difluoride
2605
(
8) Greaney, M. F.; Motherwell, W. B. Tetrahedron Lett. 2000,
1, 4463.
9) Greaney, M. F.; Motherwell, W. B. Tetrahedron Lett. 2000,
1, 4467.
(15) Haufe, G. J. Prakt. Chem. 1996, 338, 99.
4
(16) Rozen, S.; Menahem, Y. J. Fluorine Chem. 1980, 16, 19.
(17) Thomas, M. G.; Suckling, C. J.; Pitt, A. R.; Suckling, K. E.
J. Chem. Soc., Perkin Trans. 1 1999, 3191.
(
4
(
(
(
(
10) Greaney, M. F.; Motherwell, W. B.; Tocher, D. A.
Tetrahedron Lett. 2001, 42, 8523.
11) Motherwell, W. B.; Greaney, M. F.; Tocher, D. A. J. Chem.
Soc., Perkin Trans. 1 2002, 2809.
12) Tsushima, T.; Kawada, K.; Tsuji, T. Tetrahedron Lett. 1982,
(18) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2002, 2609.
(19) An equilibrium between two isomers of 7 was not observed
under the reaction conditions.
(20) Eames, J.; Coumbarides, G. S.; Suggate, M. J.;
Weerasooriya, N. Eur. J. Org. Chem. 2003, 634.
(21) A centrifuge tube with a screw cap made of Teflon FEP, a
copolymer of TFE and hexafluoropropylene, was used.
(22) Cousseau, J.; Albert, P. J. Org. Chem. 1989, 54, 5380.
(23) Stavber, S.; Sket, B.; Zajc, B.; Zupan, M. Tetrahedron 1989,
45, 6003.
23, 1165.
13) Zefirov et al. obtained dimer 5 in good yields by this method:
Zefirov, N. S.; Samoniya, N. S.; Kutateladze, T. G.;
Zhdankin, V. V. Zh. Org. Khim. 1991, 27, 220; Chem. Abstr.
1991, 115, 91694.
(
14) McClinton, M. A. Aldrichimica Acta 1995, 28, 75.
Synthesis 2005, No. 15, 2602–2605 © Thieme Stuttgart · New York