A general method of halogenation for synthesis of α-halodifluoromethyl ketones and [18F]-labeled trifluoromethyl ketones

Article abstract of DOI:10.1016/S0022-1139(03)00039-3

A convenient general method of halogenations suitable for synthesis of α-halodifluoromethyl ketones is reported. Reaction of 2,2-difluoro-1-aryl-1-trimethylsiloxyethenes (difluoro silyl enol ethers) (2a-e) with halogens at low temperature (-30 to -78 °C) produced a high yield of α-halodifluoromethyl ketones (1a-j). This one-step simple method can be highly useful for synthesis of [¹⁸F]-labeled α-trifluoromethyl ketones.

Full text of DOI:10.1016/S0022-1139(03)00039-3

Journal of Fluorine Chemistry 121 (2003) 239–243
A general method of halogenation for synthesis of a-halodifluoromethyl
ketones and [18F]-labeled trifluoromethyl ketones
G.K. Surya Prakasha,*, Jinbo Hua, Mian M. Alauddinb, Peter S. Contib, George A. Olaha
aDepartment of Chemistry, Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089-1661, USA
bDepartment of Radiology, Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089-1661, USA
Received 9 December 2002; received in revised form 20 January 2003; accepted 22 January 2003
Abstract
A convenient general method of halogenations suitable for synthesis of a-halodifluoromethyl ketones is reported. Reaction of 2,2-difluoro-
1-aryl-1-trimethylsiloxyethenes (difluoro silyl enol ethers) (2a–e) with halogens at low temperature (ꢀ30 to ꢀ78 8C) produced a high yield of
a-halodifluoromethyl ketones (1a–j). This one-step simple method can be highly useful for synthesis of [18F]-labeled a-trifluoromethyl
ketones.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Halogenation; Electrophilic fluorination; Fluorine-18
1. Introduction
([18F]-FHBG) [14] as potential PET agents for cancer diag-
nosis gene expression.
a-Trifluoromethyl ketones (TFMKs) are biologically
active compounds of increasing interest [1]. Many of these
compounds have been found to be potential hydrolytic
enzyme inhibitors, such as protease inhibitors. Due to their
unique property of forming stable tetrahedral hemiacetals or
hydrates, they act as transition-state analogues of substrates
for enzymes [1–5] TFMKs have also been demonstrated as
cytotoxic agents against human oral tumor cell lines, such as
human squamous carcinoma cells HSC-2 and salivary gland
tumor cells HSG [6]. a-TFMKs have potential for radiola-
beling with 18F, where they can be used as markers for cell
proliferation or viral infection.
Many [18F]-labeled compounds are used for in vivo non-
invasive imaging of tumor and gene expression by positron
emission tomography (PET), and thus are very useful for
diagnosis of disease and detecting metabolic parameters,
especially in the field of oncology [7]. Several types of
18F-labeled PET imaging agents have been developed,
including 18F-labeled sugars [8,9], steroids [7] proteins and
peptides [10,11]. Some of us have developed [18F]-labeled
nucleoside analogues 20-deoxy-20-fluoro-5-methyl-1-b-D-
arabinofuranosyluracil ([18F]-FMAU) [12], 9-[(3-[18F]-
fluoro-1-hydroxy-2-propoxy) methyl]guanine ([18F]-FHPG)
[13] and 9-[(4-[18F]-fluoro-3-hydroxymethyl-butyl]guanine
TFMKs are traditionally prepared from inexpensive tri-
fluoroacetic acid derivatives [15,16]. Recently, we reported
the direct preparation of TFMKs from carboxylic esters
with (trifluoromethyl)trimethylsilane (TMS-CF3) [17]. This
method has been further extended by others with CsF
catalyzed trifluoromethylation of esters [18]. However, these
methods are not suitable for synthesis of [18F]-labeled
TFMKs since it is difficult to prepare [18F]-labeled tri-
fluoroacetic acid derivatives or TMS-CF3 due to the short
half-life of 18F (t1=2 ¼ 110 min).
Herein, we report the first convenient method of fluo-
rination using 2,2-difluoro-1-aryl-1-trimethylsiloxyethenes
(2,2-difluoro silyl enol ethers) with elemental fluorine (F2).
This method is suitable for radiochemical synthesis of [18F]-
labeled TFMKs. The methodology has been extended to
synthesize other halodifluoromethyl ketones by reacting
2,2-difluoro silyl enol ethers with respective halogens, such
as Br2 and I2. The halogenodifluoromethyl ketones may have
potential biological activities.
2. Experimental
2.1. Reagents and instrumentation
* Corresponding author. Fax: þ1-213-740-6270.
All reagents and solvents were purchased from Aldrich
(Milwaukee, WI), and used without further purification,
E-mail address: gprakash@usc.edu (G.K.S. Prakash).
0022-1139/03/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00039-3

240
G.K.S. Prakash et al. / Journal of Fluorine Chemistry 121 (2003) 239–243
unless otherwise specified. Dichloromethane (CH2Cl2) and
fluorotrichloromethane (CFCl3) were distilled over calcium
hydride (CaH2), and acetonitrile (CH3CN) was distilled over
phosphorus pentoxide (P2O5) prior to use. Column chroma-
tography was performed using silica gel (60–200 meshes).
Thin layer chromatography (TLC) was performed on silica
gel plate (1 cm ꢁ 10 cm) and developed in the appropriate
solvent system (hexane:ethyl acetate, 9:1).
Proton, 13C and 19F NMR spectra were recorded on
a Bruker AMX-500 or WP-360 NMR spectrometer in
chloroform-D using tetramethysilane and trichlorofluoro-
methane as internal reference, respectively. Mass spectra
were obtained on a Hewlett-Packard 5890 gas chromato-
graph equipped with a Hewlett-Packard 5971 mass selective
detector.
described below. To a dry 250 ml Schlenk flask was added
magnesium turnings (1.45 g, 60 mmol), dry tetrahydrofuran
(THF, 120 ml) and chlorotrimethylsilane (TMSCl, 13.0 g,
120 mmol), and the flask was cooled down to 0 8C. 2,2,2-
Trifluoroacetophenone (1a, 5.2 g, 30 mmol) was added
dropwise into the flask via a syringe. After addition, the
reaction mixture was stirred for additional 1 h. The comple-
tion of the reaction was monitored by 19F NMR. The solvent
and excess TMSCl were removed under vacuum, and hexane
(50 ml) was added to the residue. Solid impurities were
filtered off by suction filtration, and the solvent was evapo-
rated to afford 2,2-difluoro-1-phenyl-1-trimethylsiloxyethene
1
(2a, 6.8 g, 99% yield). H NMR: d ¼ 0:60 (s, 9H), 7.38
(t, J ¼ 7:5 Hz, 1H), 7.47 (t, J ¼ 7:5 Hz, 2H), 7.61
(d, J ¼ 8:8 Hz, 2H); 13C NMR: d ¼ 0:02, 114.09
2
(q, JCꢀF ¼ 18:0 Hz), 125.84, 127.72, 128.25, 132.71,
1
2.2. Preparation of 2,2-difluoro-1-aryl-1-
trimethylsiloxyethenes (2a–e)
154.87 (t, JCꢀF ¼ 286:8 Hz); 19F NMR: d ¼ ꢀ100:39
2
2
(d, JFꢀF ¼ 68:0 Hz), ꢀ112.16 (d, JFꢀF ¼ 68:0 Hz). MS
(70 eV, m/z): 228 (Mþ), 213, 197, 186, 177, 131, 115, 105,
89, 81, 77, 73.
2,2-Difluoro silyl enol ethers (2a–e) were prepared via
magnesium metal mediated reductive defluorination of
TFMKs. All 2,2-difluoro silyl enol ethers were prepared
following a similar procedure. A representative method is
Other 2,2-difluoro silyl enol ethers (2b–e, entries 2–5 in
Table 1) were also characterized by spectroscopic methods
and found to be consistent with the previous report [19–23].
Table 1
Preparation of halogenated methyl ketones 1 through facile selective halogenations of 2,2-difluoro silyl enol ethers 2
Entry
1
Substrate 2
Halogenating agent
F2
Product 1
Yield (%)a
69
R ¼ Ph (2a)
2
3
F2
78b
89
Ph (2a)
SelectfluorTM
4
5
SelectfluorTM
SelectfluorTM
88
87
6
7
SelectfluorTM
Br2
90
85
Ph (2a)
8
9
Br2
Br2
I2
87
88
60
10
11
I2
39
a Isolated yield.
b Determined by 19F NMR.

G.K.S. Prakash et al. / Journal of Fluorine Chemistry 121 (2003) 239–243
241
2.3. Fluorinations of 2,2-difluoro-1-aryl-1-
trimethylsiloxyl-ethene (2a–e)
8.15 (d, J ¼ 8:0 Hz, 2H). 13C NMR: d ¼ 113:56 (t,
1JCꢀF ¼ 319:1 Hz);
128.87;
129.05;
130.61
(t,
2
3JCꢀF¼ 2:6 Hz); 135.09; 181.32 (t, JCꢀF ¼ 26:0 Hz). 19F
NMR: d ¼ ꢀ58:29. MS (70 eV, m/z): 234 (Mþ); 105
(PhCOþ); 77 (Phþ).
All experiments were performed under a similar condi-
tion. A representative method is described. Compound 2a
(200 mg, 0.88 mmol) was dissolved in dry acetonitrile
(20 ml) and cooled to ꢀ45 8C. A mixture of fluorine and
nitrogen (F2=N2 ¼ 1=4 (v/v)) was bubbled for 15 min (in
excess). The reaction mixture was warmed to room tem-
perature, and 5 ml of ice water was added. The mixture was
extracted with ether (2 ꢁ 10 ml), and the ether phase was
dried over MgSO4 and filtered. After removal of the solvent,
crude trifluoroacetophenone was obtained in 83% yield. The
crude product was purified by flash chromatography on a
silica gel column using 10% ethyl acetate in hexane as eluent
to give 106 mg 2,2,2-trifluoroacetophenone (1a) as colorless
liquid in 69% yield. 1H NMR: d ¼ 7:56 (t, J ¼ 7:8 Hz, 2H);
7.72 (t, 1H, J ¼ 7:3 Hz); 8.08 (d, J ¼ 8:1 Hz, 2H). 13C
2-Bromo-2,2-difluoro-40-trifluoromethyl-acetophenone
(1g): 1H NMR: d ¼ 7:80 (d, J ¼ 8:7 Hz, 2H); 8.26 (d,
J ¼ 8:7 Hz,
2H).
13C
NMR:
d ¼ 113:18
(t,
1JCꢀF ¼ 318:2 Hz); 123.22 (q, JCꢀF ¼ 273:2 Hz); 125.95
(q, J ¼ 4:2 Hz); 131.01 (t, J ¼ 2:8 Hz); 131.96; 136.21 (q,
J ¼ 33:3 Hz); 180.54 (t, J ¼ 27:7 Hz). 19F NMR:
d ¼ ꢀ59:22 (s, 2F); ꢀ63.96 (s, 3F). MS (70 eV, m/z): 304
(Mþ); 223 (CF3C6H4COCF2þ); 119 (CF3C6H4COþ); 91; 65.
2-Bromo-2,2-difluoro-40-methyl-acetophenone (1h): 1H
NMR: d ¼ 2:39 (s, 3H); 7.25 (d, J ¼ 8:5 Hz, 2H); 7.98
(d, J ¼ 8:0 Hz, 2H). 13C NMR: d ¼ 21:70; 113.64 (t,
1JCꢀF ¼ 318:4 Hz); 129.55; 130.65; 131.07; 146.54;
1
2
180.90 (t, JCꢀF ¼ 26:5 Hz). 19F NMR: d ¼ ꢀ57:98. MS
NMR: d ¼ 116:67 (q, JCꢀF ¼ 291:7 Hz); 129.06; 129.90;
(70 eV, m/z): 248 (Mþ); 131; 119 (CH3C6H4COþ); 91; 81;
65; 51.
1
2
130.06; 135.49; 181.05 (t, JCꢀF ¼ 35:2 Hz). 19F NMR:
d ¼ ꢀ71:85. MS (70 eV, m/z): 174 (Mþ); 123 (Mþ ꢀ 51);
105 (PhCOþ); 77; 69; 51.
2.5. Iodinations of 2,2-difluoro-1-aryl-1-
trimethylsiloxyl-ethene (2c,e)
The typical fluorination procedure with SelectfluorTM is
as follows. Compound 2a was added into a acetonitrile
solution (20 ml) of SelectfluorTM (1.0 g, 2.8 mmol) at
ꢀ78 8C (0.51 g, 2.2 mmol) in 5 ml of dichloromethane.
Then the reaction mixture was allowed to warm up to
0 8C slowly over a period of 2 h. The reaction mixture
was quenched by adding 15 ml of ice water and 20 ml of
dichloromethane. The organic phase was separated and
dried over magnesium sulfate. After removal of the solvent
and flash chromatography on silica gel using ethyl aceta-
te:hexanes (1:1) as eluent afforded 0.34 g of compound (1a)
in 89% yield.
The iodination reactions were carried out with iodine in
dichloromethane as follows. Into a 10 ml of dichloro-
methane solution of 2,2-difluoro-1-(40-chloro-phenyl)-1-tri-
methylsiloxyethene (2c, 200 mg, 0.76 mmol) at ꢀ78 8C,
was added 0.19 g iodine (0.75 mmol). After warming up
to room temperature, the reaction mixture was stirred over-
night. Then 10 ml of sodium sulfite (10% aqueous solution)
was added to remove excess iodine, followed by washing
with 5 ml of brine. The organic phase was dried over
anhydrous magnesium sulfate, and the solvent was removed
by rotary evaporator. The crude product was purified by flash
chromatography a silica gel column and eluted with pentane
to give 137 mg of the product 2-iodo-2,2-difluoro-40-chloro-
All other trifluoromethyl ketones (1b–e, entries 2–5 in
Table 1) prepared either by fluorine or SelectfluorTM were
characterized and found to be consistent with the reported
data [15].
1
acetophenone (1i) as a white solid in 60% yield. H NMR:
d ¼ 7:51 (d, J ¼ 8:9 Hz, 2H); 8.11 (d, J ¼ 8:9 Hz, 2H). 13
C
1
2.4. Brominations of 2,2-difluoro-1-aryl-
1-trimethylsiloxyl-ethene (2a,d,e)
NMR: d ¼ 95:13 (t, JCꢀF ¼ 326:4 Hz); 126.67; 129.37;
3
2
132.18 (t, JCꢀF ¼ 3:4 Hz); 1412.85; 181.29 (t, JCꢀF ¼
23:6 Hz). 19F NMR: d ¼ ꢀ55:16. MS (70 eV, m/z): 316
All bromination reactions were performed in the similar
way and a representative procedure is described. Compound
2a (6.08 g, 26.7 mmol) was dissolved in 50 ml dry CH2Cl2,
and cooled to ꢀ78 8C. Liquid bromine was added via a
syringe until the color of bromine no longer persisted. After
stirring for another 30 min, the solvent in the reaction
mixture was evaporated under vacuum, and the residue
was extracted with CH2Cl2. The organic phase was further
washed with NaHCO3, brine and water subsequently. After
drying over MgSO4 and solvent removal, the crude product
was purified by column chromatography using silica gel
and hexanes as eluent to afford 5.33 g of 2-bromo-2,2-
difluoroacetophenone (1f) in 85% yield. 1H NMR:
d ¼ 7:53 (t, J ¼ 7:8 Hz, 2H); 7.68 (t, J ¼ 7:8 Hz, 1H);
(Mþ); 177; 158; 139 (ClC6H4COþ); 127; 111; 75.
2-Iodo-2,2-difluoro-40-methyl-acetophenone (1j): 1H
NMR: d ¼ 2:46 (s, 3H); 7.32 (d, J ¼ 8:3 Hz, 2H); 8.07
(d, J ¼ 8:3 Hz, 2H). 13C NMR: d ¼ 21:89; 95.79 (t, 1JCꢀF
¼
325:5 Hz); 125.78; 129.63; 130.98 (t, J ¼ 2:5 Hz); 146.43;
2
182.04 (t, JCꢀF ¼ 22:9 Hz). 19F NMR: d ¼ ꢀ54:41. MS
(70 eV, m/z): 296 (Mþ); 177; 127; 119 (CH3C6H4COþ);
91; 65.
3. Results and discussion
Preparation of 2,2-difluoro silyl enol ethers (2a–e) is
represented in Scheme 1. Compounds 2a–e were prepared

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G.K.S. Prakash et al. / Journal of Fluorine Chemistry 121 (2003) 239–243
Scheme 1.
via magnesium metal mediated reductive defluorination of
TFMKs 1a–e, which was first developed by Uneyama’s
group [19] and later was applied by us in the preparation
of di- and monofluoromethyl ketones (Scheme 1) [20]. The
reaction was extremely facile under mild conditions and
gave excellent yield of products 2a–e (>85%). After removal
of the insoluble material (solid Mg and MgCl2) by filtration
and evaporation of the solvent fairly pure product was
obtained. These materials could be used for the next step
Scheme 3.
1
for halogenations without further purification. H and 19F
NMR spectra showed no significant impurities, with results
consistent with the literature [19,20]. These silyl enol ethers
2a–e are much more stable towards hydrolysis than normal
silyl enol ethers, which enables the simple handling of these
compounds for the subsequent studies.
(entries 7–9 in Table 1). The slow addition of bromine into
the dichloromethane solution is similar to a colorimetric
titration process, in which the completion of the reaction
could be monitored by the persistence of the bromine color.
However, iodinations produced relatively lower yields com-
pared to other halogens due to the lower electrophilicity of
iodine. The iodination reactions need longer reaction times
and gave moderate yields of iododifluoromethyl ketones
(entries 10–11 in Table 1).
The mechanism of these selective halogenation reac-
tions is shown in Scheme 3. The reaction with elemental
halogens, such as F2, Br2 and I2 is proposed to proceed
via a six-membered transition state (Eq. (1)), whereas
that with SelectfluorTM proceeds through an electrophilic
substitution.
The fluorination method using F2 has a great potential
in synthesis of [18F]-labeled a-trifluoromethyl ketones.
Reaction of these 2,2-difluoro silyl ethers with cyclotron
generated [18F]-F2 will produce [18F]-labeled TFMKs.
The bromo- and iododifluoromethyl ketones may be poten-
tially useful in biological studies and/or intermediates for
a-substituted-difluoromethyl ketones.
Scheme 2 represents the halogenation reactions of 2,2-
difluoro silyl enol ethers. Compounds 1a–j were prepared
by reaction of the respective 2,2-difluoro silyl enol ethers
(2a–e) with appropriate halogens as represented in Table 1.
For fluorination two different reagents were used to compare
the yields. Reactions were performed either in acetonitrile or
fluorotrichloromethane (Freon-11) as solvent at low tem-
peratures (Scheme 2). Experiments with F2 were performed
in CH3CN by bubbling the F2 gas as a mixture of normal
fluorine [19F]-F2, 20 vol.% in nitrogen. The bromination and
iodination procedures were similar to fluorinations, with
some minor differences. Both reactions were carried out in
dichloromethane between ꢀ78 8C and room temperature.
The fluorination reactions with F2 produced good yields
of the corresponding TFMKs (entries 1–2 in Table 1), which
were consistent with the fluorination of non-fluorinated silyl
enol ethers as reported by Purrington et al. [24]. When
Selectfluor1 [F-TEDA-BF4, N-fluoro-N-chloromethyl-
triethylenediamine bis-(tetra-fluoroborate)] was applied as
the electrophilic fluorination reagent, the reaction proceeded
also quite efficiently in acetonitrile and gave excellent yield
of TFMKs (entries 3–6 in Table 1). The bromination reac-
tions were facile in dichloromethane even at, ꢀ78 8C to
produce bromodifluoromethyl ketones in excellent yields
4. Conclusion
A general method of halogenations suitable for synthesis
of a-halo-difluoromethyl ketones has been developed. This
method is very simple and convenient, which produced good
to excellent yield of the halogenated products. Model reac-
tions with F2 are highly useful for synthesis of [18F]-labeled
a-trifluoromethyl ketones for PET iamging.
Acknowledgements
Support of our work by the Loker Hydrocarbon Research
Institute is gratefully acknowledged.
Scheme 2.

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243
[12] M.M. Alauddin, P.S. Conti, J.D. Fissekis, J. Labelled
Comp. Radiopharm. 45 (2002) 583.
References
[13] M.M. Alauddin, P.S. Conti, S.M. Mazza, F.M. Hamzeh, J.R. Lever,
Nucl. Med. Bio. 23 (1996) 787.
[1] M.J. Kawase, Syn. Org. Chem. Jpn. 59 (2001) 755.
[2] M.H. Gelb, J.P. Svaren, R.H. Abales, Biochemistry 24 (1985)
1813.
[14] M.M. Alauddin, P.S. Conti, Nucl. Med. Bio. 25 (1998) 175.
[15] X. Creary, J. Org. Chem. 52 (1987) 5026.
[3] L.H. Takahashi, R. Radhakrishnan, R.E. Rosenfield Jr., E.F. Meyer
Jr., Biochemistry 28 (1989) 7610.
[16] T. Keumi, M. Himada, M. Takahashi, H. Kitajama, Chem. Lett.
(1990) 783.
[4] T.S. Morris, S. Frormann, S. Shechosky, C. Lowe, M.S. Lall, V.
Gauss-Muller, R.H. Purcell, S.U. Emerson, J.C. Vederas, B.A.
Malcolm, Bioorg. Med. Chem. 5 (1997) 797.
[17] J. Wiedemann, T. Heiner, G. Mloston, G.K.S. Prakash, G.A. Olah,
Angew Chem. Int. Ed. 37 (1998) 820.
[18] R.P. Singh, G. Cao, R.L. Kirchmeier, J.M. Shreeve, J. Org. Chem. 64
(1999) 2873.
[5] B. Imperiali, R.H. Abeles, Biochemistry 25 (1986) 3760.
[6] M. Kawase, H. Sakagami, K. Kusama, N. Motohashi, S. Saito,
Bioorg. Med. Chem. Lett. 9 (1999) 3113.
[19] H. Amii, T. Kobayashi, Y. Hatamoto, K. Uneyama, Chem. Commun.
(1999) 1323.
[7] J.A. Katzenellenbogen, J. Fluorine Chem. 109 (2001) 49.
[8] N. Tamaki, Nippon Naika Gakkai Zasshi 89 (2000) 145.
[9] F. Helus, W. Maier-Borst, F. Oberdorfer, Dev. Nucl. Med. 22 (1992)
131.
[20] G.K.S. Prakash, J. Hu, G.A. Olah, J. Fluorine Chem. 112 (2001) 357.
[21] T. Brigaud, P. Doussot, C. Portella, Chem. Commun. 18 (1994) 2117.
[22] F. Jin, B. Jiang, Y. Xu, Tetrahedron Lett. 33 (1992) 1221.
[23] M. Yamana, T. Ishihara, T. Ando, Tetrahedron Lett. 24 (1983) 507.
[24] S.T. Purrington, N.V. Lazaridis, C.L. Bumgardner, Tetrahedron Lett.
27 (1986) 2715.
[10] S.M. Okarvi, Eur. J. Nucl. Med. 28 (2001) 929.
[11] L. Varagnolo, M.P.M. Stokkel, U. Mazzi, E.K. Pauwels, J. Nucl.
Med. Biol. 27 (2000) 103.