Synthesis of geminal difluorides by oxidative desulfurization- difluorination of alkyl aryl thioethers with halonium electrophiles in the presence of fluorinating reagents and its application for 18F- radiolabeling

Article abstract of DOI:10.1021/jo100689v

Figure presented. Various ω-substituted 1,1-difluoroalkanes are synthesized in good yields from alkyl aryl thioethers by a new oxidative desulfurization-difluorination protocol with the reagents combination of 1,3-dibromo-5,5-dimethylhydantoin (DBH) as an oxidizer and pyridine·9HF (Py·9HF) as a fluoride source. The reaction proceeds via a fluoro-Pummerer-type rearrangement followed by an oxidative desulfurization- fluorination step. Starting from α-fluorinated thioethers, this reaction is promising for ¹⁸F-labeling (τ_1/2 = 110 min) of ligands applicable for positron emission tomography (PET). Using the combination of DBH and carrier-added Py·9H[¹⁸F]F, an ¹⁸F- labeled difluoride was synthesized from the corresponding α-fluoro thioether with a radiochemical yield of 9%.

Full text of DOI:10.1021/jo100689v

pubs.acs.org/joc
Synthesis of Geminal Difluorides by Oxidative
Desulfurization-Difluorination of Alkyl Aryl Thioethers with
Halonium Electrophiles in the Presence of Fluorinating Reagents
and Its Application for 18F-Radiolabeling
‡
‡
‡
§
Verena Hugenberg,†,§ Stefan Wagner, Klaus Kopka, Otmar Schober, Michael Schafers,
€
,†,§
€
and Gunter Haufe*
†Organisch-Chemisches Institut, Westfa€lische Wilhelms-Universita€t, Corrensstrasse 40, D-48149 Mu€nster,
‡
Germany, Klinik und Poliklinik fu€r Nuklearmedizin, Universitatsklinikum, Albert-Schweitzer-Strasse 33,
€
D-48149 Mu€nster, Germany, and European Institute for Molecular Imaging,
§
€ €
€
Westfalische Wilhelms-Universitat, Mendelstrasse 11, D-48149 Munster, Germany
haufe@uni-muenster.de
Received April 9, 2010
Various ω-substituted 1,1-difluoroalkanes are synthesized in good yields from alkyl aryl thioethers
by a new oxidative desulfurization-difluorination protocol with the reagents combination of 1,3-
dibromo-5,5-dimethylhydantoin (DBH) as an oxidizer and pyridine 9HF (Py 9HF) as a fluoride
3
3
source. The reaction proceeds via a fluoro-Pummerer-type rearrangement followed by an oxidative
desulfurization-fluorination step. Starting from R-fluorinated thioethers, this reaction is promising
for 18F-labeling (τ1/2 = 110 min) of ligands applicable for positron emission tomography (PET).
Using the combination of DBH and carrier-added Py 9H[18F]F, an 18F-labeled difluoride was syn-
3
thesized from the corresponding R-fluoro thioether with a radiochemical yield of 9%.
Introduction
one of the most important tasks of current organofluorine
chemistry considering the enormous impact of fluorinated
molecules on medicinal and materials chemistry,1 and many
efficient and selective methods have been developed in recent
years.2 Among them, different oxidative fluorinations of sul-
fur compounds and oxidative desulfurization-fluorination
methods have come into focus.3 Originally electrophiles such
as xenon difluoride,4 N-fluoropyridinium salts,5 or electro-
chemical oxidation in the presence of different fluorinating
reagents6 were applied for R-fluorination of sulfides. Later
The development of new methods for the introduction
of one or several fluorine atoms into organic compounds is
(1) Recent monographs: (a) Banks, R. E.; Smart, B. E.; Tatlow, J. C.
Organofluorine Chemistry. Principles and Commercial Applications; Plenum
Press: New York, 1994. (b) Biomedical Frontiers of Fluorine Chemistry ;
Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium Series 639;
American Chemical Society: Washington, DC, 1996. (c) Kirsch, P. Modern
Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004. (d) Uneyama, K.
Organofluorine Chemistry; Blackwell: Oxford, 2006. (e) Begue, J. P.; Bonnet-
Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; John Wiley &
Sons: Hoboken, 2008. (f) Fluorine and Health. Molecular Imaging, Bio-
medical Materials and Pharmaceuticals; Tressaud, A., Haufe, G., Eds.;
Elsevier: Amsterdam, 2008.
ꢀ
ꢀ
(3) (a) Kuroboshi, M.; Kanie, K.; Hiyama, T. Adv. Synth. Catal. 2001,
343, 235–244. (b) Shimizu, M.; Hiyama, T. Angew. Chem. 2005, 117, 218–
234. ; Angew. Chem., Int. Ed. 2005, 44, 214-231.
(4) (a) Zupan, M. J. Fluorine Chem. 1976, 8, 305–309. (b) Marat, R. K.;
Janzen, A. F. Can. J. Chem. 1977, 55, 3031–3034. (c) Janzen, A. F.; Wang,
P. M. C.; Lemire, A. E. J. Fluorine Chem. 1983, 22, 557–559.
(5) Umemoto, T.; Tomizawa, G. Bull. Chem. Soc. Jpn. 1986, 59, 3625–
3629.
(6) (a) Brigaud, T.; Laurent, E. Tetrahedron Lett. 1990, 31, 2287–2290.
(b) Fuchigami, T.; Shimojo, M.; Konno, A.; Nakagawa, K. J. Org. Chem.
1990, 55, 6074–6075. (c) Fuchigami, T.; Konno, A.; Nakagawa, K.; Shimojo,
M. J. Org. Chem. 1995, 59, 5937–5941. (d) Narizuka, S.; Koshiyama, H.;
Konno, A.; Fuchigami, T. J. Fluorine Chem. 1995, 73, 121–127. (e) Haufe, G.
J. Prakt. Chem. 1996, 338, 99–113.
(2) Recent monographs: (a) Olah, G. A.; Chambers, R. D.; Prakash,
G. K. S. Synthetic Fluorine Chemistry; John Wiley & Sons: New York, 1992.
(b) Chemistry of Organic Fluorine Compounds II. A Critical Review;
ꢀ
Hudlicky, M., Pavlath, A. E., Eds.; ACS Monograph 187; American
Chemical Society, Washington, DC, 1995. (c) Enantiocontrolled Synthesis
of Fluoro-Organic Compounds. Stereochemical Challenges and Biomedical
Targets; Soloshonok, V. A., Ed.; John Wiley & Sons: Chichester, 1999.
(d) Fluorine-Containing Synthons; Soloshonok, V. A., Ed.; ACS Symposium
Series 911; American Chemical Society: Washington, DC, 2005. (e) Current
Fluoroorganic Chemistry. New Synthetic Directions, Technologies, Materials,
and Biological Applications; Soloshonok, V. A., Mikami, K., Yamazaki, T.,
Welch, J. T., Honek, J. F., Eds.; ACS Symposium Series 949; American
Chemical Society: Washington, DC, 2006.
6086 J. Org. Chem. 2010, 75, 6086–6095
Published on Web 08/26/2010
DOI: 10.1021/jo100689v
r
2010 American Chemical Society

Hugenberg et al.
JOCArticle
other oxidants such as selectfluor7 or difluoroiodoarenes8
were shown to be useful. Recently, combinations of chemical
oxidants such as 1,3-dibromo-5,5-dimethylhydantoin (DBH)
combined with tetrabutylammonium dihydrogentrifluo-
ride (TBAH2F3)9 or iodine pentafluoride (IF5) in the pre-
of aldehyde thioacetals in the presence of Et3N 3HF.21 Also
3
several other oxidants such as SO2ClF, SO2Cl2, or NOBF4 in
combination with Olah’s reagent16,22 or with TBAH2F323 or
the hexafluoropropene-diethylamine reagent24 as well as
bromine trifluoride25 are suitable for this transformation.
Recently, difluoromethyl- and trifluorothioethers have been
synthesized by reaction of alkyl aryl thioethers with IF5.11
Here we report on a new oxidative desulfurization-
difluorination protocol of alkyl aryl thioethers leading to
gem-difluoroalkanes. Preliminary results have been commu-
nicated recently.26a This method might be useful for radio-
labeling with [18F]fluoride.
sence of triethylamine tris(hydrogenfluoride) (Et3N 3HF)10
3
have been applied. Treatment of alkyl aryl sulfides with IF5
in an inert solvent at elevated temperature gave rise to aryl
polyfluoroalkyl sulfides.11 It has been shown that these reac-
tions proceed similarly to the original fluoro-Pummerer re-
arrangement of sulfoxides with diethylaminosulfurtrifluoride
(DAST).12
The oxidative desulfurization-fluorination reaction is another
efficient protocol for the introduction of one or more fluo-
rine atoms into organic molecules. The original hazardous
Results and Discussion
Chemistry. To develop a convenient method for the selec-
tive introduction of one or more fluorine atoms into the
activated R-position, we reacted various types of alkyl aryl
thioethers with several electrophiles in the presence of Olah’s
reagent as a fluoride source.
13
reagents such as CF3OF and/or HF/F2 were replaced by
more convenient ones such as N-bromosuccinimide (NBS)/
Olah’s reagent (Py 9HF) or DAST in due course.14 Also the
3
combinations of methyl fluorosulfonate and cesium fluo-
ride15 or nitrosonium tetrafluoroborate (NOBF4) with Olah’s
reagent16 or application of p-iodotoluene difluoride17 resul-
ted in a transformation of arylthioethers into the corres-
ponding fluorides by substitution of the arylthio group.
Particularly the difluoromethyl group became interesting
recently because of its biological properties. This group is
isopolar and almost isosteric with a carbonyl group, and
several compounds bearing this moiety are metabolically
more stable than the original biologically active molecules
and/or are potent enzyme inhibitors.18 Consequently, a variety
of methods for their preparation have been described.19
Originally, Sondej and Katzenellenbogen transformed 1,3-
dithiolanes or 1,3-dithianes to gem-difluorides by treatment
with a halonium ion donor (DBH, NBS) and a fluoride
source.20 Moreover, it is known that aliphatic gem-difluoro
compounds can be prepared by anodic fluorodesulfurization
The initial reaction of p-nitrophenyl undecyl thioether (1a)
as a sample molecule with N-iodosuccinimide (NIS) and
Olah’s reagent was not selective but gave mixtures of di- and
trifluoro thioethers 2 and 3 and the gem-difluoroalkane 4
depending on the molar ratio of substrate and reagents (Table 1).
In addition, the R-iodinated thioether 5 and the sulfoxide 6
were found in the crude product mixture among other
unidentified trace products (Scheme 1).
TABLE 1. Reaction of 1a with NIS and Olah’s Reagent under Various
Conditions
crude product mixture (GC %)
Py 9HF
3
NIS (equiv) (equiv)
1a
2
3
4
5
6
others
1.1
2.2
4.4
6.0
2.2
4.4
4.4
6.0
55
33
12
42
41
3
2
2
7
28
19
11
12
3
3
12
28
1
23
43
6
14
(7) Lal, G. S. J. Org. Chem. 1993, 58, 2791–2796.
(8) (a) Greaney, M. F.; Motherwell, W. B. Tetrahedron Lett. 2000, 41,
4463–4466. (b) Greaney, M. F.; Motherwell, W. B. Tetrahedron Lett. 2000,
41, 4467–4470. (c) Greaney, M. F.; Motherwell, W. B.; Tocher, D. A.
Tetrahedron Lett. 2001, 42, 8523–8526.
SCHEME 1. Reaction of 1a with NIS and Olah’s Reagent
(9) (a) Furuta, S.; Kuroboshi, M.; Hiyama, T. Tetrahedron Lett. 1995, 36,
8243–8246. (b) Furuta, S.; Kuroboshi, M.; Hiyama, T. Bull. Chem. Soc. Jpn.
1998, 71, 2687–2694.
(10) (a) Yoneda, N.; Fukuhara, T. Chem. Lett. 2001, 222–223. (b) Ayuba,
S.; Yoneda, N.; Fukuhara, T.; Hara, S. Bull. Chem. Soc. Jpn. 2002, 75, 1597–
1603.
(11) (a) Ayuba, S.; Fukuhara, T.; Hara, S. Org. Lett. 2003, 5, 2873–2874.
(b) Ayuba, S.; Hiramatsu, C.; Fukuhara, T.; Hara, S. Tetrahedron 2004, 60,
11445–11451.
(12) (a) McCarthy, J. R.; Peet, N. P.; LeTourneau, M. E.; Inbasekaran,
M. J. Am. Chem. Soc. 1985, 107, 735–737. (b) Wnuk, S. F.; Robins, M. J.
J. Org, Chem. 1990, 55, 4757–4760. (c) Robins, M. J.; Wnuk, S. F. J. Org.
Chem. 1993, 58, 3800–3801. (d) Aki, S.; Kita, Y. Top. Curr. Chem. 2007, 274,
35–76.
(13) Kollonitsch, J.; Marburg, S.; Perkins, L. M. J. Org. Chem. 1976, 41,
3107–3111.
(14) Nicolaou, K. C.; Dolle, R. E.; Papahatjis, D. P.; Randall, J. L. J. Am.
Chem. Soc. 1984, 106, 4189–4192.
(15) Ichikawa, J.; Sugimoto, K.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1987, 1985–1988.
(16) York, C.; Prakash, G. K. S.; Olah, G. A. Tetrahedron 1996, 52, 9–14.
(17) Caddick, S.; Gazzard, W. B.; Motherwell, W. B.; Wilkinson, J. A.
Tetrahedron 1996, 52, 149–156.
(18) (a) Biomedicinal Aspects of Fluorine Chemistry; Filler, R., Kobayashi,
Y., Eds.; Kodansh & Elsevier Biomedical: Tokyo, 1982. (b) Welch, J. T.
Tetrahedron 1987, 43, 3123–3197. (c) Synthesis and Function of Fluorinated
Compounds; Ishikawa, N., Ed.; CMC: Tokyo, 1987.
(19) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619–8683.
(20) Sondej, S. C.; Katzenellenbogen, J. A. J. Org. Chem. 1986, 51, 3508–
3513.
The mechanism of formation of the di- and trifluoro thio-
ethers is similar to the one proposed by Hara et al.11 The intro-
duction of the first fluorine atom proceeds according to the
mechanism of the fluoro-Pummerer rearrangement (Scheme 2).12
The sulfur in 1a is attacked by the electrophile NIS to form
the sulfonium intermediate I, which gives the vinylic sulfide 7
(21) Yoshiyama, T.; Fuchigami, T. Chem. Lett. 1992, 1995–1998.
(22) Prakash, G. K. S.; Hoole, D.; Reddy, V. P.; Olah, G. A. Synlett 1993,
691–693.
(23) Kuroboshi, M.; Hiyama, T. Synlett 1991, 909–910.
(24) Shimizu, M.; Maeda, T.; Fujisawa, T. J. Fluorine Chem. 1995, 71, 9–12.
(25) Rozen, S. Acc. Chem. Res. 2005, 38, 803–812.
(26) (a) Hugenberg, V.; Haufe, G. Synlett 2009, 106–108. (b) Hugenberg,
V.; Haufe, G. J. Fluorine Chem. 2010, 131, 942–950.
J. Org. Chem. Vol. 75, No. 18, 2010 6087

Hugenberg et al.
JOCArticle
SCHEME 2. Reaction Mechanism of the Formation of Difluoro Thioether 2, Trifluoro Thioether 3, and Difluoride 4
after hydrogen iodide elimination and deprotonation of the
resonance stabilized carbenium-sulfonium ion II. This un-
saturated thioether (unidentified, but might be among the
side products) is then attacked again by an iodonium ion to
give the stabilized intermediate III, which finally adds fluo-
ride in R-position to sulfur. Anchimeric assistance of the
arylthio group leads to elimination of iodide with formation
of an episulfonium ion IV. Subsequent nucleophilic ring-
opening by fluoride attack at the terminal position results
in the migration of the arylthio group and formation of the
difluorinated thioether 2. With an increasing excess of the
reagents compound 2 reacts further to give 3 as shown in
Since we were unable to increase the selectivity of the reaction
by variation of the reaction conditions (time, temperature,
application of Et3N 3HF instead of Olah’s reagent), we chan-
3
ged from iodonium to bromonium ions as electrophiles. How-
ever, reactions of 1a with NBS or DBH and Et3N 3HF were
3
unselective and incomplete after 16 h at room temperature and
5hat50°C. Finally, the combination of DBH and Olah’s reagent
was found to be most selective to form the gem-difluoroalkane 4.
However, under these conditions another side product, the gem-
bromofluoroalkane 9, was identified. The reaction of the thio-
ether 1a with excess DBH/Olah’s reagent was complete after 3 h,
giving a 4:1 ratio of the products 4 and 9 (Table 2, entry 1).
Scheme 2 and Table 1. Moreover, with excess of NIS/Py
Contrary to our expectation, addition of Et3N 3HF as
3
3
9HF also the gem-difluoroalkane 4 is formed. This com-
pound is derived from intermediate II by R-fluorination
to form 8a and subsequent oxidative desulfurization-
difluorination. From the intermediate II also the side pro-
duct 5 (not isolated, but suggested by GC-MS of the crude
product mixture) can arise by iodide addition. Analogous
products were not found in the reactions of alkyl aryl
thioethers with IF5.11 The formation of sulfoxide 6 can be
explained by hydrolysis of intermediate I during aqueous
workup. This means that the steps succeeding the initial
electrophilic attack on 1 are slow. This assumption is sup-
ported by the fact that quenching of the reaction (ratio of 1a:
NIS:Olah’s reagent =1:4.4:4.4) with water after 1 h of reac-
tion time at room temperature gave the sulfoxide 6 almost
exclusively. The oxidation of alkyl aryl thioethers by halo-
gens in the presence of water has already been described in
the literature.27
additional more nucleophilic fluoride source28 did not in-
crease the portion of 4 but increased that of 9 leading to an
approximate 1:1 mixture of 4 and 9 (entry 2). The same effect
was observed when AgF or KHF2 was added (entries 3 and
4). The ratio of 4:9 was not significantly changed. We do not
have an explanation for this effect yet, since addition of
tetrabutylammonium bromide (TBAB) or potassium bro-
mide increased the ratio of 4:9 but simultaneously yielded a
bigger amount of other side products (entries 5 and 6). The
use of NBS as a source of the electrophile led to much slower
reactions and increased amounts of byproduct and was less
selective with regard to the formation of difluoride 4.
Further optimization experiments (see Table S1 in Sup-
porting Information) showed that the reaction of the thio-
ether 1a with excess DBH/Olah’s reagent was complete after
1 h at room temperature (or 30 min at 45 °C), giving a 89:11
mixture of products 4 and 9 (Table 3, entry 1).26a Also other
(27) Kowalski, P.; Mitka, K.; Ossowaska, K.; Kolarska, Z. Tetrahedron
2005, 61, 1933–1953.
(28) (a) Sattler, A.; Haufe, G. J. Fluorine Chem. 1994, 69, 185–190.
€
(b) Lubke, M.; Skupin, R.; Haufe, G. J. Fluorine Chem. 2000, 102, 125–133.
6088 J. Org. Chem. Vol. 75, No. 18, 2010

Hugenberg et al.
JOCArticle
TABLE 2. Oxidative Desulfurization-Difluorination of the Thioether 1a in the Presence of Different Additives
crude product mixture (GC %)
entry
additive
additive (equiv) DBH (equiv) Py 9HF (equiv)
reaction conditions
4
9
6
10
others
3
1
2
3
4
5
6
3.0
3.0
3.0
3.0
3.0
3.0
6.0
6.0
6.0
6.0
6.0
4.0
30 min, 0 °C, 2.5 h, rt
1 h, rt
30 min, 0 °C, 4 h, rt
30 min, 0 °C, 1 h, rt
30 min, 0 °C, 20 h, rt
30 min, 0 °C, 3 d, rt
67
39
36
37
54
61
19
33
35
31
18
19
14
22
18
23
28
26
Et3N 3HF
AgF
KHF2
TBAB
KBr
1.0
1.0
1.0
1.0
1.0
5
3
1
11
6
3
TABLE 3. Oxidative Desulfurization-Difluorination of p-Substituted Alkyl Aryl Thioethers 1a-d with DBH and Olah’s Reagent
crude product (GC %)a
entry
compd
X
DBH (equiv)
Py 9HF (equiv)
3
reaction conditions
4
9
yield (%)b
1
2
3
4
5
6
7
1a
1a
1a
1b
1b
1c
1d
NO2
NO2
NO2
Cl
Cl
F
CH3
3.0
3.0
3.0
3.0
3.0
3.0
3.0
6.0
6.0
2.2
6.0
2.2
6.0
6.0
1 h, rt
89
88
68
86
94
83
92
11
12
32
14
6
8026
c
c
77
c
15 min, 40 W, 37 °C
15 min, 100 W, 45 °C
4 h, 30 °C
30 min, 100 W, 45 °C
4 h, 30 °C
30 h, 29 °C
17
8
75
c
aThe ratio (GC) calibrated to 100% (approximately 10% of unidentified byproduct was also found in the crude product mixture after aqueous
workup). bIsolated yield of difluoride 4. cAliquots for reaction control were taken; yields were not determined.
alkyl aryl thioethers 1b-d bearing different substituents in
the para position did react similarly but needed longer
reaction time and higher temperature to go to completion.
Less electron-withdrawing or electron-donating para sub-
stituents slowed down the reaction rate but did not signifi-
cantly affect the ratio of 4:9. The reason for the slower
reaction might be the stabilization of the intermediates of
types I and II (Scheme 3) by substituents with positive
inductive or resonance effects. Thus, elimination of hydro-
gen bromide from I or addition of fluoride or bromide to II
becomes slower. Deprotonation of II to form 7 (cf. Scheme 2)
or succeeding products seems not to occur under these
conditions. Under microwave irradiation the reaction of
Olah’s reagent from a bottle opened several times already
(“old”) led to increased formation of bromofluoride 9 (Table 4,
entries 1 and 2), whereas use of Olah’s reagent from a freshly
opened bottle (“fresh”) showed the opposite selectivity
(entry 3). The conversion of 1a with DBH, triethylamine
trishydrofluoride, and “old” Olah’s reagent also resulted in
preferred formation of gem-bromofluorides. With 3 equiv of
DBH, 5 equiv of Et3N 3HF, and 6 equiv of Py 9HF a ratio
3
3
of difluoride to bromofluoride of 23:77 was obtained (entry
4). An additional byproduct of this reaction was the dibro-
mofluoroundecane 11 (12%, for the mechanism of forma-
tion see ref 26b). The reaction with DBH and Et3N 3HF
3
exclusively led to sulfoxide 6 as the sole product isolated after
17 h of reaction time and hydrolytic workup (entry 6).
An explanation for the formation of bromide ions in
reaction mixtures of NBS and fluorinating agents was given
by Guerrero et al.29 An analogous mechanism is possible
with DBH and triethylamine trishydrofluoride, which is less
thioether 1a with 3.0 equiv of DBH and 6.0 equiv of Py 9HF
3
was complete after 15 min (40 W, 37 °C), and even a
minimum of 2.2 equiv of Olah’s reagent led to full conversion
of 1a in 15 min at 45 °C and 100 W. The reaction time for the
thioether 1b with 3.0 equiv of DBH and 2.2 equiv of Olah’s
reagent could also be reduced to 30 min at 45 °C and 100 W.
The formation of the gem-bromofluoride 9 as a byproduct
could not be suppressed completely in the reactions of the
thioethers 1a-d. However, the CHBrF group represents
also an interesting unit for the synthesis of R-fluorinated
thioethers or other monofluorinated compounds. Therefore,
we also optimized the reaction conditions for the synthesis
of gem-bromofluoroalkanes realizing that the product ratio
significantly depends on the quality of Olah’s reagent. Using
acidic as compared to Py 9HF, so that the generation of
3
bromide ions and consequently the formation of the bromo-
fluoride 9 is favored (see also the discussion in ref 28b).
Repetition of the experiment (entry 4) with “fresh” Olah’s
reagent and excess triethylamine trishydrofluoride yielded
the gem-difluoride 4 as the major product (Table 4, entry 5).
(29) Camps, F.; Chamorro, E.; Gasol, V.; Guerrero, A. J. Org. Chem.
1989, 54, 4294–4298.
J. Org. Chem. Vol. 75, No. 18, 2010 6089

Hugenberg et al.
JOCArticle
SCHEME 3. Mechanism of Formation of Difluoride 4 and Bromofluoride 926
TABLE 4. Optimization of Reaction Conditions Towards gem-Bromofluoride 9
crude product (GC %)
H2O
(equiv)
DBH
(equiv)
Et3N 3HF
3
Py 9HF
3
entry
1a (mmol)
(equiv)
(equiv)
reaction conditions
4
9
6
10
others
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
0.5
0.25
0.5
1.0
2.0
2.0
2.0
3.0
3.0
2.0
3.0
3.0
3.0
4.0 (old)a
5.0 (old)a
4.0 (fresh)
6.0 (old)a
6.0 (fresh)
30 min, 0 °C; 4.5 h, rt
30 min, 0 °C; 4.5 h, rt
30 min, 0 °C; 4.5 h, rt
30 min, 0 °C; 1 h, rt
30 min, 0 °C; 1 h, rt
30 min, 0 °C; 17 h, rt
30 min, 0 °C; 20 h, rt
30 min, 0 °C; 20 h, rt
30 min, 0 °C; 20 h, rt
18
18
76
20
68
58
53
16
68
19
10
16
7
8
3
7
5
5
5.0
5.0
12.0
6.0
6.0
6.0
12b
3
10
80
14
13
9
20
0.67
0.55
0.44
6.0 (fresh)
6.0 (fresh)
6.0 (fresh)
8
19
32
53
53
52
5
15
7b
aOlah’s reagent from a bottle already opened several times. b1,1-Dibromo-1-fluoroundecane (11).
From these results we suspected that traces of water in the
reaction mixture might be responsible for the significant
change of selectivity. Therefore, a small amount of water
was added to the reaction mixture (Table 4). For a 0.25 mmol
terminally substituted with bromine in the alkyl chain, the
difluoride 13 was generally favored over the formation of
gem-bromofluoroalkane 14 (Table 5). Again higher temper-
ature and longer reaction times were necessary to completely
convert starting thioethers with a less electron-withdrawing
or with an electron-releasing substituent in the para position
of the phenyl ring (Table 5, entries 2-4). Elevation of the
reaction temperature to 30 °C did not significantly influence
the chemoselectivity of the reaction.
The reactions of thioethers substituted by other terminal
functional groups on the alkyl chain such as ester, ether, and
phthalimide (15a-e and 15g) yielded also predominately
difluorides (Table 5, entries 9-15). With terminal alcohol
or acid functions (Y = OH, COOH), complex mixtures of
unidentified products were formed. Deprotection of the phtha-
limido compounds 16e and 17e with hydrazine provided the
terminal amines 16f and 17f in high yield. The oxidative
desulfurization-difluorination of the thioether 15g with a
p-nitrophenylether at the terminal position of the alkyl chain
was characterized by a high selectivity for gem-difluorides
16g1 and 16g2, formed by additional mono- and dibromina-
tion of the phenyl ring with excess DBH.
scale reaction with 3 equiv of DBH, 6 equiv of Py 9HF, and
3
6 equiv of Et3N 3HF, the addition of 0.67 equiv of water
3
showed the best results with regard to the selective formation
of the bromofluoride 9. Simple scale-up of this reaction was
not possible, because more water prevented complete con-
version of the thioether 1a to the gem-difluoride 4 or gem-
bromofluoride 9, and the sulfone 10 became the major
reaction product after hydrolysis. Stepwise increase of the
reaction scale showed that addition of 0.55 equiv of water led
to the best selectivity for 9 in a 0.5 mmol batch, whereas for a
1.0 mmol batch 0.44 equiv of water was shown to be optimal.
These optimization experiments showed that the addition
of traces of water resulted in an increased chemoselectivity
for bromofluoride 9. Further addition of water resulted in
incomplete reaction, formation of sulfoxide 6 or sulfone 10,
and a bigger amount of other byproduct depending on the
amount of DBH. No increase in selectivity toward the gem-
bromofluoride 9 was achieved by this way.
To make the new oxidative desulfurization-difluorina-
tion protocol suitable for the preparation of substituted
compounds, which are useful as building blocks,30 we pre-
pared several ω-substituted starting materials such as 12a-h,
15a-e, and 15g. For the reactions of thioethers 12, which are
Similarly to the mechanism shown in Scheme 2, the mono-
fluoride 8a should be formed from 1a as an intermediate via
cations I and II (Scheme 3) according to a Pummerer-like
rearrangement with simultaneous oxidation of the R-carbon
and fluoride introduction. This compound is subsequently
oxidized at sulfur by another bromonium species giving,
after a second fluoro-Pummerer rearrangement, the terminal
difluorides 4 (pathway a). Addition of bromide to the same
(30) Podichetty, A. K.; Faust, A.; Kopka, K.; Wagner, S.; Schober, O.;
€
Schafers, M.; Haufe, G. Bioorg. Med. Chem. 2009, 17, 2680–2688.
6090 J. Org. Chem. Vol. 75, No. 18, 2010

Hugenberg et al.
JOCArticle
TABLE 5. Oxidative Desulfurization-Fluorination of p-Substituted Alkyl Aryl Thioethers 12a-h, 15a-e, and 15g with Various Terminal Groups on the
Alkyl Chain
crude product (GC %)a
entry
compd
X
Y
n
DBH (equiv)
Py 9HF (equiv)
reaction conditions
13/16
14/17
yield (%)b
3
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12f
12g
12h
15a
15b
15c
15d
15e
d
NO2
Cl
F
CH3
NO2
NO2
F
NO2
NO2
Cl
F
Cl
Cl
d
Cl
Br
Br
Br
Br
Br
Br
Br
Br
COOMe
COOMe
COOMe
OMe
10
10
10
10
9
3
3
13
8
8
8
9
9
9
10
5.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
d
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
d
2 h, rt
81
87
93
86
86
52
75
48
60
95
80
94
88
66
96e
96f
19
13
7
14
14
48
25
52
40
5
20
6
12
34
4
68
5 h, 30 °C
5 h, 30 °C
29 h, rt
2 h, rt
20 h, rt
20 h, rt
20 h, rt
4.5 h, rt
18 h, rt
18 h, rt
18 h, rt
18 h, rt
d
c
9226
c
8626
51
42
23
9
54
10
11
12
13
14
15
8026
c
93
PhthN
NH2
OPhNO2
8826
56
15g
3.0
6.0
18 h, rt
38e
4
57f
aThe ratio is calibrated to 100%. Approximately 10% of unidentified byproduct was also found by GC of the crude product mixture after aqueous
b
c
d
workup. Isolated yield of difluoride 13 or 16. Aliquots for reaction control were taken; yields were not determined. The mixture of phthalimido
derivatives 16e and 17e was used as starting material to form 16f and 17f by hydrazinolysis (cf. Experimental Section). eCompound 16g1 with
monobrominated phenyl ring (ratio by 19F NMR). fCompound 16g2 with dibrominated phenyl ring (ratio by 19F NMR).
TABLE 6. Oxidative Desulfurization Fluorination of 8b
p-chlorophenyl-(1-fluoroundec-1-yl)thioether (8b) was reacted
with 1.5 equiv of DBH and 3 equiv of Olah’s reagent in dry
dichloromethane at room temperature for 20 h (Table 6). 1,1-
Difluoroundecane (4) and 1-bromo-1-fluoroundecane (9)
were obtained in a ratio of 95:5. By mircowave irradiation
the amount of fluorinating reagent and the reaction time could
be reduced to 1.1 equiv and 40 min. Thus, R-fluoro thioethers 8
were verified as intermediates of the oxidative desulfuriza-
tion-difluorination reaction of thioethers 1 to gem-difluoride
4 and gem-bromofluoride 9 and substituted analogues.
Moreover, these experiments proved the fast introduction
of a second fluorine atom into R-fluoro thioethers by oxida-
tive desulfurization-fluorination. This might be an interest-
ing method for the introduction of the short living 18F isotope
(τ1/2 = 110 min) into biologically relevant compounds for
positron emission tomography (PET) applications. There-
fore this reaction was tested with compound 8e in order to
develop a new carrier-added radiofluorination method with
[18F]fluoride.31
crude product
(GC %)a
DBH
entry (equiv)
Py 9HF
3
(equiv)
reaction conditions
4
9
1
2
3
1.5
1.5
1.5
3.0
2.0
1.1
20 h, rt
40 min, 45 °C, 100 W
40 min, 45 °C, 100 W
95
90
93
5
10
7
aThe ratio is calibrated to 100%, <5% impurities.
sulfonium ion formed in the first reaction step leads to the
gem-bomofluorides 9 (pathway b).26 An alternative route for
the formation of the gem-bromofluoride 9 is the addition of
bromide instead of fluoride to the intermediate II followed
by a fluoro-Pummerer rearrangement. Compounds 13 or 16
and 14 or 17, respectively, are formed analogously.
To prove this mechanism, reactions of the thioether 1a
were carried out with less DBH and Olah’s reagent. With 1.0
and 2.0 equiv of DBH and 1.0 and 2.0 equiv of Py 9HF, the
R-fluoro thioether 8a was found as the main product after 1 h
at room temperature. The isolation of 8a failed because of
HF elimination during column chromatography on silica
gel. However, the synthesis of the R-fluoro thioethers 8b,d,e,
18b, and 19b,g (see Supporting Information) was possible
from thioethers 1b,d,e, 12b, and 15b,g using DAST and
SbCl3 according to a method by Wnuk and Robins.12b
To prove that R-fluoro thioethers of type 8 are intermediates
in the formation of the gem-difluorides, by way of example
Radiochemistry. In initial experiments reactions of the
R-fluorinated thioether 8e with X[18F]F (X=Br, Cl) generated
in situ from DBH or N-chlorosuccinimide (NCS), K[18F]F,
and sulfuric acid as described by Katzenellenbogen et al.32
3
(31) For reviews on radiofluorination methods, see: (a) Lasne, M.-C.;
ꢀ
Perrio, C.; Rouden, J.; Barre, L.; Roeda, D.; Dolle, F.; Crouzel, C. Top. Curr.
Chem. 2002, 222, 201–258. (b) Dolle, F.; Roeda, D.; Kuhnast, B.; Lasne,
ꢀ
ꢀ
M.-C. In Fluorine and Health. Molecular Imaging, Biomedical Material and
Pharmaceuticals; Tressaud, A., Haufe, G., Eds.; Elsevier: Amsterdam, 2008;
pp 3-65.
(32) (a) Chi, D. Y.; Kiesewetter, D. O.; Katzenellenbogen, J. A.
€
J. Fluorine Chem. 1986, 31, 99–113. (b) Chi, D. Y.; Lindstrom, P. J.; Choe,
Y. S.; Bonasera, T. A.; Welch, M. J.; Katzenellenbogen, J. A. J. Fluorine
€
Chem. 1995, 71, 143–147. (c) Choe, Y. S.; Lindstrom, P. J.; Chi, D. Y.;
Bonasera, T. A.; Welch, M. J.; Katzenellenbogen, J. A. J. Med. Chem. 1995,
38, 816–825.
J. Org. Chem. Vol. 75, No. 18, 2010 6091

Hugenberg et al.
JOCArticle
TABLE 7. Results of Radiofluorination of 8e with DBH and Carrier-Added
Maximal radiochemical yield of 9.0% [18F]16e was achieved
Py 9H[18F]F
with 8-fold excess of Py 9H[18F]F.
3
3
Experimental Section
Chemistry. General analytical methods and equipment as well
as general procedure for oxidative desulfurization-difluorina-
tion with DBH/Olah’s reagent are given in Supporting Informa-
tion. For some long chain compounds 13C NMR signals at δ ∼
29 ppm do have multiple intensity.
Py 9H[18F]F
CH2Cl2
(μL)
rcya,c
(%)
rcpb,c
(%)
3
entry
(μL)
product
Radiochemistry. Radiosyntheses were carried out using an
automated PET tracer synthesizer. The recorded data were
processed by a commercial software. Identification of the radio-
synthesized compounds [18F]8e and [18F]16e was performed by
gradient radio-HPLC system with an UV detector, a γ-detector,
and a Nucleosil 100-5 C18 column (250 mm ꢀ 4.6 mm). Detec-
tion was conducted at λ = 254 nm. The solvents used were A
(waterþ0.1% TFA) and B (CH3CNþ0.1% TFA). The mobile
phase was a gradient using 40:60 A/B to 1:99 A/B mixture over
20 min, holding for 18 min and back to 40:60 A/B mixture in
2 min at a common flow rate of 1.5 mL/min. Radiochemical
yield and purity were determined by the analysis of the HPLC
chromatograms of the γ-channel.
Fluorination of the Thioethers with NIS and Olah’s Reagent.
General Procedure. The reaction was carried out in a 100-mL
Teflon flask. To a solution of thioether (0.5 mmol) in absolute
CH2Cl2 (5 mL) was added Olah’s reagent (for equivalents used,
see Table 1) via a polypropylene/polyethylene syringe. The
mixture was cooled to 0 °C, and NIS (for the amounts, see
Table 1) was added. After 30 min at 0 °C the reaction mixture
was allowed to warm to room temperature and was stirred at
this temperature overnight. Then ice-water was added, and the
reaction mixture was neutralized with concentrated aqueous
NH3. The phases were separated, and the aqueous layer was
extracted with Et2O (3 ꢀ 20 mL). The combined organic layer
was washed with 0.1 N HCl (2 ꢀ 20 mL) and 5% aqueous
NaHCO3 (2ꢀ20 mL) and dried over anhydrous MgSO4. After
concentration under reduced pressure, the products 2, 3, and 4
were separated by column chromatography (silica gel, cyclo-
hexane/ethyl acetate, 40:1) or HPLC (cyclohexane).
1-3
4-6
7-9
2.5
5.0
10.0
150
300
150
[
[
[
18F]8e
6.9 ( 1.5
78 ( 3
65 ( 14
61 ( 24
18F]16e 9.0 ( 1.4d
18F]16e 5.5 ( 0.4d
arcy = radiochemical yield (decay corrected). brcp= radiochemical
purity of the prepurified (C18 cartridge) reaction solution determined by
HPLC. cValues are the mean ( standard deviation of three experiments.
dCompound [18F]8e was formed as a byproduct with 0.5% rcy.
for halofluorination of olefins were investigated. Unfortu-
nately, the expected difluoro compound 16e was not formed
under these conditions. Therefore, DBH (3 equiv) and
pyridinium [18F]poly(hydrogen fluoride) (Py 9H[18F]F) pre-
3
pared as previously described33 was utilized for the desulfuri-
zation-fluorination of 8e (25 μmol batch) and [18F]16e was
obtained. The results of the radiochemical reactions (average
of three identical experiments) with carrier-added Py
9H[18F]F and 8e are outlined in Table 7.
The product spectrum of the reactions depended on the
3
amount of carrier-added Py 9H[18F]F in the reaction mix-
3
ture. Small excess (entries 1-3, 4 equiv of HF) resulted in
a fluorine-18 for fluorine-19 exchange and formation of
[18F]8e as the radiochemical main product. Here, the difluo-
ride [18F]16e was not observed. On the other hand quad-
ruplication of Py 9H[18F]F (entries 7-9, 16 equiv of HF)
3
provided the desulfurization-fluorination product [18F]16e
with a radiochemical yield (rcy) of 5.5% (decay corrected,
dc). When a median amount of Py 9H[18F]F (entries 4-6,
3
8 equiv of HF) was used and the solvent amount was doubled
from 150 to 300 μL, rcy of [18F]16e was increased to 9.0%
(dc). Compared to the experiments with the small excess of
fluorination reagent (entries 1-3), only traces (rcy ∼0.5%)
of the isotopic exchange product [18F]8e were formed in
experiments 4-9.
1,1-Difluoroundec-2-yl-(4-nitrophenyl)thioether (2). Follow-
ing the general procedure the reaction was carried out in a 0.5
mmol scale using Olah’s reagent (0.23 mL, 1.00 mmol, 2.0 equiv)
and NIS (0.55 mmol, 1.1 equiv). After HPLC purification
(cyclohexane) the product was obtained as a colorless oil (20 mg,
12%). 1H NMR (CDCl3, 500 MHz): δ 0.88 (t, 3 H, CH3, 3JH,H
=
6.9 Hz), 1.30 (br s, 12 H, CH2), 1.40-1.97 (m, 4 H, CH2), 3.45(m,
1 H, CH), 5.85 (td, 1 H, CH, 2JH,F=56 Hz, 3JH,H=4 Hz), 7.50 (d,
Conclusion
2 H, CH, 3JH,H =8.8 Hz), 8.15 (d, 2 H, CH, 3JH,H =8.9 Hz). 13
C
NMR (CDCl3, 126 MHz): δ 14.1 (q), 22.7 (t), 26.6, 26.9, 27.9 (t,
Different ω-substituted alkyl aryl thioethers can be di-
rectly transformed to terminal 1,1-difluoroalkanes by two
succeeding oxidations of sulfur by an electrophile and
fluoro-Pummerer-like rearrangements using the reagents
combination of DBH and Olah’s reagent. In contrast, both
the anodic and other chemical desulfurization-fluorination
reactions do need thioacetals as starting materials.21-25 In
general this desulfurization-fluorination reaction is also
possible starting from intermediate R-fluorinated alkyl aryl
thioethers. On the basis of the latter transformation, a new
radiofluorination protocol was developed. The radiolabeled
difluoride [18F]16e was synthesized from R-fluorothioether
3JC,F =3.2 Hz), 29.2, 29.3, 29.4 (t), 31.8 (t), 50.4 (t, 2JC,F =21.3
Hz), 116.3 (t, JC,F = 246 Hz), 124.0 (d), 129.5 (d), 144.5 (s),
1
146.2 (s). 19F NMR (CDCl3, 470 MHz): δ -119.6 (ddd, 1 F,
2
3
2JF,F = 277.4 Hz, JH,F = 56.4 Hz, JH,F = 12.6 Hz), -119.8
(ddd, 1 F, 2JF,F =277.4 Hz, 2JH,F =56.4 Hz, 3JH,F =12.6 Hz).
MS (EI-GC inlet): m/z (%) 345 (97) [Mþ], 328 (18) [Mþ -OH],
315 (18) [Mþ - NO], 294 (64) [Mþ - CHF2], 260 (11) [C11H12F2-
NO2Sþ], 232 (3) [C9H8F2NO2Sþ], 218 (4) [C8H6F2NO2Sþ], 207
(12), 168 (13) [C7H6NO2Sþ], 155 (100) [HSC6H5-NO2þ], 125 (39)
[C9H17þ], 124 (34), 109 (12) [C6H5Sþ], 97 (18) [C7H13þ], 83 (24)
[C6H11þ], 69 (33) [C5H9þ], 57 (38) [C4H9þ], 55 (52) [C4H7þ], 51 (5)
[HCF2þ], 43 (53) [C3H7þ] 41 (53) [C3H5þ]. HRMS (ESI): [M þ
Naþ] calcd for C17H25F2NO2SNaþ 368.1466, found 368.1466.
1,1,2-Trifluoroundec-2-yl-(4-nitrophenyl)thioether (3). The pro-
duct was obtained (entry 4, Table 1) as a colorless oil. Yield: 137 mg
(35%). 1H NMR (CDCl3, 500 MHz): δ 0.85 (m, 3 H, CH3),
1.19-1.38 (m, 12 H, CH2), 1.54-1.70 (m, 2 H, CH2), 1.82-2.18
(m, 2H, CH2), 5.55 (ddd, 1H, CH, 2JH,F=55.8Hz, 2JH,F=54.4 Hz,
8e by combination of DBH and carrier-added Py 9H[18F]F.
3
(33) (a) Josse, O.; Labar, D.; Georges, B.; Gregoire, V.; Marchand-
Brynaert, J. Bioorg. Med. Chem. 2001, 9, 665–675. (b) Cheguillaume, A.;
ꢀ
Gillart, J.; Labar, D.; Gregoire, V.; Marchand-Brynaert, J. Bioorg. Med.
Chem. 2005, 13, 1357–1367.
6092 J. Org. Chem. Vol. 75, No. 18, 2010

Hugenberg et al.
JOCArticle
3JH,F = 2.8 Hz), 7.79 (d, 2 H, CH2, 3JH,H =8.8 Hz), 8.22 (d, 2 H,
3JH,H=8.8 Hz). 13C NMR (CDCl3, 126 MHz): δ 14.1 (q), 22.7 (t),
22.9 (td, 3JC,F=2.6 Hz), 29.2, 29.4, 29.5, 29.7 (t), 31.8 (t), 32.6 (tdd,
2JC,F = 20.9 Hz, 3JC,F = 1.6 Hz), 104.3 (sddd, 1JC,F = 228.6 Hz,
2JC,F =25.9 Hz, 2JC,F =23.9 Hz), 112.3 (dddd, 1JC,F =253.1 Hz,
1JC,F=248.9 Hz, 2JC,F=40.3 Hz), 123.8 (d), 136.2 (d, 4JC,F=2.0
Hz), 136.5 (s), 148.5 (s). 19FNMR(d6-Benzol, 470 MHz): δ-126.8
93 (5)[C4H7F2þ], 87 (79) [C5H8Fþ], 67 (52) [C5H7þ], 59 (79)
[C3H4Fþ], 55 (79) [C4H7þ], 51 (39) [CHF2þ], 41 (88) [C3H5þ].
1,5-Dibromo-1-fluoropentane (14f). Yield: 57 (46%). 1H NMR
(CDCl3, 300 MHz): δ 1.18-1.34 (m, 2 H, CH2), 1.60-1.72 (m,
2 H, CH2) 1.77-1.99 (m, 2 H, CH2), 3.41 (t, 2 H, CH2, 3JH,H=6.6
Hz), 6.46 (dt, 1 H, CH, 2JH,F=50.2 Hz, 3JH,H=5.3Hz). 13CNMR
(CDCl3, 75 MHz): δ 20.9 (td, 3JC,F=5.6 Hz), 32.1 (t), 32.7 (t), 33.3
2
2
1
(ddd, 1 F, JF,F = 284.1 Hz, 2JH,F = 54.3 Hz, 3JF,F = 13.4 Hz),
(td, JC,F = 21.1 Hz), 94.75 (dd, JC,F = 252.4 Hz). 19F NMR
-133.3 (ddd, 1 F, 2JF,F =284.3 Hz, 2JH,F =55.7 Hz, 3JF,F =14.4
Hz), -143.0 (m, 1 F). MS (EI-GC inlet): m/z (%) 363 (48) [Mþ],
346 (8) [Mþ-OH], 343 (4) [Mþ-HF], 312 (12) [Mþ-CHF2], 292 (7)
[Mþ-HF-CH2], 281 (12), 231 (7), 207 (36) [C11H18F3þ], 181 (5)
[C9H12F3þ], 165 (9) [C8H12F3þ], 155 (100) [C6H5NO2Sþ], 124 (41)
[C6H5NO2Sþ-NO], 109 (15) [C6H5Sþ], 81 (19), 71 (33) [C5H11þ],
67 (15) [C5H7þ], 55 (33) [C4H7þ], 43 (51) [C3H7þ], 41 (42) [C3H5þ].
HRMS (ESI): [MþNaþ] calcd for C17H24F3NO2SNaþ 386.1372,
found 386.1370.
(CDCl3, 282 MHz): δ -131.7 (m, 1 F, 2JH,F = 50.3 Hz, 3JH,F
=
18.9 Hz). MS (EI-GC inlet): m/z (%) þ250/248/246 (<0.1/<0.1/
<0.1) [Mþ], 169/167 (16/16) [M -Br3 ], 149/147 (13/13)
[C5H8Brþ], 109/107 (9/9) [C2H4Brþ], 95/93 (5/5) [CH2Brþ], 87
(100) [C5H8Fþ], 67 (47) [C5H7þ], 59 (63) [C3H4Fþ], 41 (75)
[C3H5þ].
15-Bromo-1,1-difluoropentadecane (13h). The reaction was
carried out in a 0.135 mmol scale with 4-nitrophenyl-(15-bromo-
pentadec-1-yl)thioether (12h) in 24 h at room temperature. After
column chromatography (silica gel, pentane) a colorless oil of
13h was isolated. Yield: 10.2 mg (23%). As the major product
the bromofluoride 1,15-dibromo-1-fluorododecane (14h) was
formed in this reaction. 1H NMR (CDCl3, 300 MHz): δ 1.18-
1.38 (m, 16 H, CH2), 1.38-1.63 (m, 4 H, CH2), 1.71-1.93 (m,
1,1-Difluoroundecane (4). Yield: 21 mg (11%, from entry 4,
Table 1). The analytical data agree with those described in our
earlier work.26a
Oxidative Desulfurization-Difluorination. General Procedure.
The general procedure of this reaction and compounds 4, 13a-e,
16a-c, and 16e was described in our earlier work.26a
4 H, CH2), 2.03-2.40 (m, 2 H, CH2), 3.41 (t, 2 H, CH2, 3JH,H
=
C
6.9 Hz), 5.79 (tt, 1 H, CH, 2JH,F=57.0 Hz, 3JH,H=4.6 Hz). 13
1-Bromo-1-fluoroundecane (9). Isolated by column chromato-
graphy (silica gel, pentane) from the optimization reaction (Table 4,
NMR (CDCl3, 75 MHz): δ 22.1 (tt, 3JC,F =5.5 Hz), 28.2, 28.7,
28.8, 29.0, 29.3, 29.4, 29.5, 29.6, 29.7 (t), 32.8 (t), 34.0 (t), 34.1 (tt,
1
entry 9). Yield: 90 mg (36%). H NMR (CDCl3, 300 MHz): δ
0.89 (t, 3 H, CH3, 3JH,H =6.9 Hz), 1.19-1.40 (m, 12 H, CH2,),
1.42-1.61 (m, 2 H, CH2), 1.94-2.36 (m, 4 H, CH2), 6.45 (dt, 1 H,
CH, 2JH,F=50.5Hz, 3JH,H=5.5Hz). 13CNMR(CDCl3, 75MHz):
δ 14.1 (q), 22.7 (t), 25.0 (td, 3JC,F=3.9 Hz), 28.7, 29.3, 29.4, 29.5
1
2JC,F = 20.5 Hz), 117.5 (dt, JC,F = 238.8 Hz). 19F NMR
(CDCl3, 282 MHz): δ -116.2 (dt, 2 F, 2JH,F = 57.0 Hz, 3JH,F
=
17.6 Hz). MS (EI-GC inlet): m/z (%) 328/326 (<0.1/<0.1)
[Mþ], 247 (<0.1) [C15H29F2þ], 205 (<0.1) [C12H23F2þ], 191 (1),
[C11H21F2þ], 177 (1) [C10H19F2þ], 163 (3) [C9H17F2þ], 149 (13)
[C8H15F2þ], 137/135 (83/100) [C4H8Brþ], 121 (17) [C6H11F2þ],
107 (9) [C5H9F2þ], 69 (25) [C5H9þ], 57 (33) [C4H9þ], 55 (39)
[C4H7þ], 41 (23) [C3H5þ].
2
1
(t), 31.9 (t), 40.6 (td, JC,F = 18.6 Hz), 95.8 (dd, JC,F = 252.4
Hz). 19F NMR (CDCl3, 282 MHz): δ -130.7 (ddd, 1 F, 2JH,F
=
50.5 Hz, 3JH,F = 20.4 Hz, 3JH,F = 17.4 Hz). MS (EI-GC inlet):
m/z (%) 254/252 (<0.1/<0.1) [Mþ], 183/181 (1/1) [C6H11BrFþ],
169/167 (2/2) [C5H9BrFþ], 155/153 (9/9) [C4H7BrFþ], 131 (24)
[C8H13Fþ], 117 (38) [C7H14Fþ], 103 (22) [C6H12Fþ], 97 (48)
[C7H13þ], 85 (50) [C6H13þ], 71 (58) [C5H11þ], 57 (81) [C4H9þ],
55 (89) [C4H7þ], 43 (81) [C3H7þ], 41 (100) [C3H5þ].
1,15-Dibromo-1-fluoropentadecane (14h). Yield: 23.3 mg (45%).
1H NMR (CDCl3, 300 MHz): δ 1.18-1.38 (m, 16 H, CH2),
1.38-1.63 (m, 4 H, CH2), 1.71-1.93 (m, 4 H, CH2), 2.03-2.40
(m, 2 H, CH2), 3.41 (t, 2 H, CH2, 3JH,H =6.9 Hz), 6.45 (dt, 1 H,
2
3
1,1-Dibromo-1-fluoroundecane (11). Found as a byproduct of
the optimization reaction (Table 4, entry 9) for the synthesis of
1-bromo-1-fluoroundecane (9). Isolated by column chromato-
graphy (silica gel, pentane) as a colorless oil. Yield: 17 mg (5%).
1H NMR (CDCl3, 500 MHz): δ 0.89 (t, 3 H, CH3, 3JH,H=7.0 Hz),
1.21-1.35 (m, 12 H, CH2), 1.36-1.43 (m, 2 H, CH2), 1.64-1.72
(m, 2 H, CH2), 2.60-2.73 (m, 2 H, CH2). 13C NMR (CDCl3, 126
MHz): δ 14.1 (q), 22.7 (t), 26.6 (td, 3JC,F = 2.3 Hz), 28.2, 29.3,
CH, JH,F = 50.4 Hz, JH,H = 5.5 Hz). 13C NMR (CDCl3, 75
MHz): δ 25.0 (td, 3JC,F=3.9 Hz), 28.2, 28.7, 28.8, 29.0, 29.3, 29.4,
29.5, 29.6, 29.7 (t), 32.8 (t), 34.0 (t), 40.6 (td, 2JC,F=18.9 Hz), 95.8
(dd, 1JC,F = 252.3 Hz). 19F NMR (CDCl3, 282 MHz): δ -130.7
(ddd, 1 F, 2JH,F=50.5 Hz, 3JH,F=20.4 Hz, 3JH,F=17.5 Hz). MS
(EI-GC inlet): m/z (%) 388/386 (<0.1/<0.1) [Mþ], 309/308 (2/2)
[Mþ - Br•], 367/265 (2/2) [C12H23BrFþ], 253/251 (3/3) [C11H22-
BrFþ], 239/237 (3/3) [C10H19BrFþ], 223/221 (3/3) [C9H17BrFþ],
207/205 (5/5) [C8H15BrFþ], 193/191 (5/5) [C8H16Brþ], 179/175
(6/5) [C7H14Brþ], 149/147 (12/12) [C5H10Brþ], 137/135 (41/41)
[C4H8Brþ], 69 (68) [C5H9þ], 57 (65) [C4H9þ], 55 (100) [C4H7þ], 41
(56) [C3H5þ].
29.4, 29.5 (t), 31.9 (t), 53.1 (td, 2JC,F=18.6 Hz), 97.2 (sd, 1JC,F
320.9 Hz). 19F NMR (CDCl3, 282 MHz): δ -43.4 (t, 1 F, 3JH,F
=
=
15.5 Hz). MS (EI-GC inlet): m/z (%) 334/332/330 (<0.1/<0.1/
<0.1) [Mþ], 253/251 (10/11) [Mþ-Br], 211/209 (7/7) [C8H15BrFþ],
197/195 (10/10) [C7H13BrFþ], 183/181 (7/7) [C7H11BrFþ], 177/
175 (8/8) [C7H4Brþ], 139/137 (6/7) [C3H3BrFþ], 109 (30), 95 (54)
[C7H11þ], 85 (78) [C6H13þ], 71 (100) [C5H11þ], 57 (90) [C4H9þ],
41 (57) [C3H5þ].
Methyl 11-Bromo-11-fluoroundecanoate (17a). 1H NMR
(CDCl3, 300 MHz): δ 1.29-1.48 (m, 12 H, CH2), 1.57-1.66
=
(m, 2H, CH2), 1.74-1.89 (m, 2 H, CH2), 2.30 (t, 2 H, CH2, 3JH,H
7.5 Hz), 3.67 (s, 3 H, CH3), 6.45 (dt, 1 H, CH, 2JH,F=50.5 Hz,
5-Bromo-1,1-difluoropentane (13f). The reaction was carried
out in a 0.5 mmol scale with 4-nitrophenyl-(5-bromopent-1-yl)-
thioether (12f) in 20 h at room temperature. In addition to the
title compound 13f, 1,5-dibromo-1-fluoropentane 14f was
found as the major byproduct; 13f was isolated as a colorless
oil by column chromatography (silica gel, pentane). Yield: 48 mg
(51%). 1H NMR (CDCl3, 300 MHz) δ 1.18-1.34 (m, 2 H, CH2),
1.60-1.72 (m, 2 H, CH2) 1.77-1.99 (m, 2 H, CH2), 3.41 (t, 2 H,
3JH,H =5.5 Hz). 13C NMR (CDCl3, 75 MHz): δ 25.0 (td, 3JC,F
=
4.0 Hz), 24.9 (t), 29.0, 29.1, 29.2 (t), 34.0 (t), 40.6 (td, 2JC,F =18.7
1
Hz), 51.4 (s), 95.7 (dd, JC,F = 252.4 Hz), 174.3 (s). 19F NMR
(CDCl3, 282 MHz): δ -130.8 (ddd, 1 F, 2JH,F =50.5 Hz, 3JH,F
=
3
20.4 Hz, JH,F = 17.5 Hz). MS (EI-GC inlet): m/z (%) 298/296
(<0.1/<0.1) [Mþ], 267/265 (2/2) [C11H19BrFOþ], 217 (4)
[C12H22FOþ], 185 (3) [C11H21O2þ], 101 (4) [C5H9O2þ], 87 (34)
[C4H7O2þ], 74 (100) [C3H6O2þ], 69 (11) [C5H9þ], 59 (12)
[C2H3O2þ], 55 (15) [C4H7þ], 43 (11) [C3H7þ], 41 (14) [C3H5þ].
HRMS (ESI): [M þ Naþ] calcd for C12H22BrFO2Naþ 321.0660/
319.0679, found 321.0655/319.0669.
CH2, 3JH,H=6.6 Hz), 5.80 (tt, 1 H, CH, 2JH,F=56.7 Hz, 3JH,H
=
4.4 Hz). 13C NMR (CDCl32, 75 MHz): δ 20.9 (tt, 3JC,F=5.6 Hz),
1
32.1 (t), 32.7 (t), 33.3 (tt, JC,F = 21.1 Hz), 117.0 (dt, JC,F
=
=
239.2 Hz). 19FNMR (CDCl3, 282 MHz): δ-116.4 (dt, 2 F, 2JH,F
1,1-Difluoro-11-methoxyundecane (16d). The reaction was carried
out in a 2.00 mmol scale with 4-chorophenyl-(11-methoxyundec-
1-yl)thioether (15d) in 17 h at room temperature. Besides 16d,
3
56.7 Hz, JH,F = 17.4 Hz). MS (EI-GC inlet): m/z (%) 188/
186 (3/3) [Mþ], 168/166 (2/2) [Mþ-HF], 107 (100) [C5H9F2þ],
J. Org. Chem. Vol. 75, No. 18, 2010 6093

Hugenberg et al.
JOCArticle
1-bromo-1-fluoro-11-methoxyundecane (17d, 6%) was formed as
the major byproduct. After column chromatography (silica gel,
pentane/diethylether 90:1) the product was isolated as a colorless oil.
Yield: 413 mg (93%). 1H NMR (CDCl3, 300 MHz): δ 1.24-1.38
(m, 12H,CH2), 1.38-1.62 (m, 4 H, CH2), 1.71-1.91 (m, 2 H, CH2),
3.33 (s, 3 H, CH3), 3.36 (t, 2 H, CH2, 3JH,H =6.6 Hz), 5.79 (tt, 1 H,
CH, 2JH,F=57.0Hz, 3JH,H=4.6Hz). 13CNMR(CDCl3, 75MHz):
δ22.1 (tt, 3JC,F=5.4 Hz), 26.1 (t), 29.0, 29.3, 29.4, 29.5, 29.6 (t), 34.1
(tt, 2JC,F =20.6 Hz), 58.5 (q), 72.9 (t), 117.4 (dt, 1JC,F =238.6 Hz).
19F NMR (CDCl3, 282 MHz): δ -116.2 (dt, 2 F, 2JH,F =57.0 Hz,
3JH,F =17.6 Hz). MS (EI-GC inlet): m/z (%) 222 (2) [Mþ], 205 (6)
[Mþ-OH], 190 (6) [Mþ-CH4O], 162 (9) [C9H16F2þ], 134 (7)
[C7H12F2þ], 120 (12) [C6H10F2þ], 83 (29) [C6H11þ], 69 (30)
[C6H9þ], 55 (38) [C4H7þ], 45 (100) [C2H5Oþ], 41 (37) [C3H5þ].
HRMS(ESI):[MþNaþ] calcdforC12H24F2ONaþ 245.1687, found
245.1686.
1,1-Difluoro-11-aminoundecane (16f). A mixture of 1,1-difluoro-
11-N-phthalimidylundecane and 1-bromo-1-fluoro-11-N-phthal-
imidylundecane26a (16e/17e, 60 mg, 0.175 mmol) and hydrazine
hydrate (11 μL, 11.2 mg, 0.175 mmol) was dissolved in ethanol
(2 mL) and stirred at room temperature overnight. Then water
(5 mL) was added and the aqueous phase was extracted with
dichloromethane (3 ꢀ 5 mL). The combined organic phases were
washed with water (2ꢀ5 mL) and dried over anhydrous MgSO4.
After concentration under reduced pressure, the product was
obtained as a colorless liquid (difluoride/bromofluoride, 66:34).
Yield: 20 mg (56%). 1H NMR (CD2Cl2, 300 MHz): δ 1.25-1.37
(m, 14 H, CH2), 1.37-1.56 (m, 2 H, CH2), 1.62-1.95 (m, 2 H,
1.47-1.66 (m, 4 H, CH2), 1.67-2.00 (m, 4 H, CH2), 4.09 (t, 2 H,
CH2, 3JH,H=6.5 Hz), 5.79 (tt, 1 H, CH, 2JH,F=57.0 Hz, 3JH,H
=
4.5 Hz), 8.41 (s, 2 H, CH). 13C NMR (CDCl3, 75 MHz): δ 22.1 (tt,
3JC,F =5.4 Hz), 25.7 (t), 29.0, 29.3, 29.4, 29.5, 29.7, 30.0 (t), 34.0
(tt, 2JC,F=20.6 Hz), 74.4 (t), 117.4 (dt, 1JC,F=238.7 Hz), 118.7
(d), 128.1 (s), 144.0 (s), 159.2 (s). 19F NMR (CD2Cl2, 282 MHz):
2
3
δ -116.2 (dt, 2 F, JH,F = 57.0 Hz, JH,F = 17.6 Hz). HRMS
(ESI): [M þ Naþ] calcd for C18H25Br2F2NO3Naþ 526.0021/
524.0042/522.0061, found 526.0029/524.0046/522.0070.
4-Chlorophenyl-(1-fluoroundec-1-yl)thioether (8b). According
to the method described by Wnuk and Robins12b a flame-dried
Schlenk flask was purged with argon and charged with anhy-
drous CH2Cl2 (1 mL), 4-chlorophenylundec-1-ylthioether (0.25
mmol), and SbC13 (4 mg, 0.02 mmol, 0.07 equiv). DAST (0.46 mL,
57 mg, 0.35 mmol, 1.40 equiv) was injected via a polypropylene/
polyethylene syringe, and the reaction mixture was stirred at
ambient temperature for 24 h. Then ice-cold saturated aqueous
NaHCO3 (10 mL) was added. The mixture was extracted with
CH2C12 (2ꢀ20 mL), and the combined organic phase was washed
with saturated aqueous NaHCO3 (10 mL), H2O (10 mL), and
saturated aqueous NaCl (10 mL), dried (MgSO4), and evapora-
ted to give a brown oil. Because of HF elimination the purifica-
tion by column chromatography was not possible. Yield (crude
1
product): 79 mg (100%). H NMR (CDCl3, 300 MHz): δ 0.88
(t, 3 H, CH3, 3JH,H=6.9 Hz), 1.04-1.28 (m, 14 H, CH2), 1.36-
1.56 (m, 2 H, CH2) 1.74-2.09 (m, 2 H, CH2), 5.75 (ddd, 1 H, CH,
2JH,F =55.6 Hz, 3JH,H =6.8 Hz, 3JH,H =6.0 Hz), 7.30 (d, 2 H,
CH, 3JH,H=8.6 Hz), 7.44 (d, 2 H, CH, 3JH,H=8.6 Hz). 13C NMR
(CDCl3, 75 MHz): δ 14.1 (q), 22.6 (t), 25.3 (td, 3JC,F =3.2 Hz),
29.0, 29.3, 29.4, 29.5 (t), 31.8 (t), 35.2 (td, 2JC,F=21.8 Hz), 101.7
CH2), 2.67 (t, 2 H, CH2, 3JH,H=6.8 Hz), 5.78 (tt, 1 H, CH, 2JH,F
=
57.1 Hz, 3JH,H=4.6 Hz). 13C NMR (CD2Cl2, 75 MHz): δ 21.9 (tt,
3JC,F =5.5 Hz), 26.6 (t), 28.8, 29.1, 29.2, 29.3 (t), 33.4 (t), 33.8 (tt,
2JC,F =20.5 Hz), 41.9 (t), 117.4 (dt, 1JC,F =238.4 Hz). 19F NMR
1
4
(dd, JC,F = 218.3 Hz), 129.1 (d), 131.5 (dd, JC,F = 2.2 Hz),
133.4 (sd, 3JC,F=2.1 Hz), 134.1 (s, C-1). 19F NMR (CDCl3, 282
MHz): δ-145.7 (ddd, 1 F, 2JH,F=55.6Hz,3JH,F=19.6 Hz, 3JH,F
=
(CD2Cl2, 282 MHz): δ -116.1 (dt, 2 F, 2JH,F = 57.1 Hz, 3JH,F
=
15.3 Hz). MS (EI-GC inlet): m/z(%) 316 (17) [Mþ], 296 (71) [Mþ-
HF], 183 (58) [C9H8ClSþ], 157 (17) [C7H6ClSþ], 144 (100)
[C6H5ClSþ], 108 (13) [C6H4Sþ], 97 (42) [C7H13þ], 83 (33)
[C6H13þ], 69 (25) [C5H9þ], 55 (25) [C4H7þ], 41 (33) [C3H5þ].
4-Tolyl-(1-fluoro-11-methoxyundec-1-yl)thioether (8d), 4-Chloro-
phenyl-(11-bromo-1-fluorododec-1-yl)thioether (18b), Methyl 11-
(4-chlorophenylthio)-11-fluoroundecanoate (19b), and 4-Chloro-
phenyl-[12-(4-nitrophenoxy)-1-fluorododec-1-yl]thioether (19g).
For spectroscopic data, see Supporting Information.
17.8 Hz). MS (EI-GC inlet): m/z (%) 207 (7) [Mþ], 187 (2)
[C11H22FNþ], 162 (1) [C9H16F2þ], 148 (2) [C8H15F2þ], 142 (6)
[C9H15Fþ], 128 (6) [C8H14Fþ], 114 (11) [C7H16Nþ], 100 (25)
[C6H14Nþ], 86 (57) [C5H12Nþ], 55 (100) [C4H7þ], 43 (13) [C3H7þ],
41 (13) [C3H5þ]. HRMS (ESI): [MþHþ] calcd for C11H23F2NHþ
208.1858, found 208.1871.
12-(2-Bromo-4-nitrophenoxy)-1,1-difluorododecane (16g1) and
12-(2,6-Dibromo-4-nitrophenoxy)-1,1-difluordodecane (16g2). The
reaction was carried out in a 0.5 mmol scale with 4-chlorophenyl-
[12-(4-nitrophenoxy)dodec-1-yl]thioether (15g) in 20 h at room
temperature. After column chromatography (silica gel, pentane/
diethylether, 30:1) two ring-brominated difluorides were isolated.
Bromofluorides brominated additionally in the ring were obtained
as byproducts (4%).
4-Chlorophenyl-(1-fluoro-11-N-phthalimidylundec-1-yl)thioether
(8e). According to the method described by Wnuk and Robins,12b
compound 8e was synthesized from 2-[11-(4-chlorophenylthio)-
undecyl]isoindoline-1,3-dione (15e) in a 0.25 mmol scale. Because
of HF elimination the purification by column chromatography was
not possible. Yield (crude product): 115 mg (100%). Mp 70 °C. 1H
NMR (CDCl3, 300 MHz): δ 1.07-1.40 (m, 12 H, CH2), 1.40-1.54
(m, 2 H, CH2), 1.58-1.74 (m, 2 H, CH2) 1.91 (m, 1H, CH2), 2.97
(m, 1 H, CH2), 3.67 (t, 2 H, CH2, 3JH,H =7.3 Hz), 5.73 (ddd, 1 H,
CH, 2JH,F=55.6 Hz, 3JH,F=6.8 Hz, 3JH,H=6.0 Hz), 7.29 (d, 2 H,
CH, 3JH,H =8.5 Hz), 7.43 (d, 2 H, CH, 3JH,H =8.5 Hz), 7.70 (dd,
12-(2-Bromo-4-nitrophenoxy)-1,1-difluorododecane (16g1).
The product was obtained as an orange solid. Yield: 81 mg
(38%). Mp 65 °C. 1H NMR (CDCl3, 300 MHz): δ 1.32 (br s, 12
H, CH2), 1.40-1.64 (m, 4 H, CH), 1.68-1.98 (m, 4 H, CH2), 4.13
(t, 2 H, CH2, 3JH,H=6.4 Hz), 5.79 (tt, 1 H, CH, 2JH,F=57.0 Hz,
3JH,H=4.5 Hz), 6.93 (d, 1 H, CH, 3JH,H=9.1 Hz), 8.18 (dd, 1 H,
2H,CH,3JH,H=5.4Hz,4JH,H=3.1Hz),7.83(dd,2H,CH,3JH,H
=
CH, 3JH,H =9.1 Hz, 4JH,H =2.7 Hz), 8.45 (d, 1 H, CH, 4JH,H
=
5.4 Hz, 4JH,H =3.1 Hz). 13C NMR (CDCl3, 75 MHz): δ 25.2 (td,
3JC,F =3.2 Hz), 26.7 (t), 28.5 (t), 28.9, 29.0, 29.2, 29.3 (t), 35.1 (td,
2JC,F =21.9 Hz), 38.0 (t), 101.6 (dd, 1JC,F = 218.3 Hz), 123.0 (s),
129.1 (d), 131.5 (sd 3JC,F=2.1 Hz), 132.2 (s), 133.4 (dd, 4JC,F=2.0
Hz), 133.8 (d), 134.1 (s), 168.4 (s). 19F NMR (CDCl3, 282 MHz): δ
-145.9 (ddd, 1 F, 2JH,F =55.6 Hz, 3JH,F =19.6 Hz, 3JH,F =15.3
Hz). MS (EI-GC-inlet): m/z (%) 461 (<0.1) [Mþ], 443 (25) [Mþ-
HF], 298 (4) [C17H26ClSþ], 230 (1) [C14H16NO2þ], 216 (2) [C13H14-
NO2þ], 202 (3) [C12H12NO2þ], 160 (100) [C9H6NO2þ], 148 (32)
[C8H6NO2þ], 144 (27) [C6H5ClSþ], 77 (4) [C6H5þ], 55 (5) [C4H7þ].
HRMS(ESI):[MþNaþ] calcdforC25H29ClFNO2SNaþ: 484.1484;
found: 484.1479.
2.7 Hz). 13C NMR (CDCl3, 75 MHz): δ 22.1 (tt, 3JC,F=5.4 Hz),
25.8 (t), 28.8, 29.0, 29.2, 29.3, 29.4 (t), 34.1 (tt, 2JC,F =20.6 Hz),
70.1 (t), 111.4 (d), 112.1 (d), 117.5 (dt, 1JC,F =238.6 Hz), 124.6
(d), 129.1 (s), 141.3 (s), 164.6 (s). 19F NMR (CD2Cl2, 282 MHz):
δ -116.3 (dt, 2 F, 2JH,F=57.0 Hz, 3JH,F=17.7 Hz). MS (EI-GC
inlet): m/z (%) 423/421 (14/14) [Mþ], 219/217 (17/14)
[C6H4BrNO3þ], 204 (17) [C12H22F2þ], 161 (11) [C9H15F2þ],
147 (25) [C8H13F2þ], 121 (44) [C6H11F2þ], 83 (33) [C6H13þ], 69
(50) [C5H9þ], 55 (100) [C4H7þ], 41 (72) [C3H5þ]. HRMS (ESI):
[M þ Naþ] calcd for C18H26BrF2NO3Naþ 446.0937/444.0956,
found 446.0942/444.0960.
12-(2,6-Dibromo-4-nitrophenoxy)-1,1-difluorododecane (16g2).
The product was obtained as an orange oil. Yield: 144 mg
Oxidative Desulfurization-Fluorination of 4-Chlorophenyl-
(1-fluorundec-1-yl)-thioether (8b). Olah’s reagent (0.09 mL,
1
(57%). H NMR (CDCl3, 300 MHz): δ 1.33 (m, 12 H, CH2),
6094 J. Org. Chem. Vol. 75, No. 18, 2010

Hugenberg et al.
JOCArticle
0.375 mmol, 3 equiv) was added to a solution of 4-chlorophenyl-
(1-fluorundec-1-yl)thioether (8b, 40 mg, 0.125 mmol) in dry
CH2Cl2 (2.5 mL) in a Telfon flask via a polypropylene/polyethylene
syringe. DBH (54 mg, 0.188 mol, 1.5 equiv) was added, and the
mixture was stirred at room temperature overnight. Then ice-
water was added, and the reaction mixture was neutralized with
concentrated NH3 solution. The phases were separated, and the
aqueous layer was extracted with Et2O (3 ꢀ 20 mL). The com-
bined organic phases were washed with 0.1 N HCl (2 ꢀ 20 mL)
and 5% aqueous NaHCO3 (2 ꢀ 20 mL) and dried over anhy-
drous MgSO4. After concentration under reduced pressure, the
product, 1,1-difluoroundecane (4), was obtained as a colorless
oil. 1-Bromo-1-fluoroundecane (9, 5%, 19F NMR) was formed
as a byproduct.
was added. After the addition of DBH (21.5 mg, 75 μmol,
3 equiv) and CH2Cl2 (50-100 μL) the tube was sealed, and the
mixture was left in an ultrasound bath for 30 min at 35 °C. The
reaction was quenched and diluted by injection of acetonitrile
(1 mL) and water (10 mL). The mixture was passed through a
Waters Sep-Pak Plus C18 cartridge. The cartridge was washed
with a mixture of acetonitrile (1 mL) and water for injection
(10 mL) and eluted with acetonitrile (3.0 mL). The eluate was
evaporated to dryness in vacuo and redissolved in acetonitrile
(300 μL). The preparation was completed within approximately
71 min. The solution was assayed concerning radiochemical
yields and purities of the products [18F]8e (tR ([18F]8e)=30.0 min)
and [18F]16e (tR ([18F]16e) = 21.5 min) with a radio-RP-HPLC
system (see General Methods, Radiochemistry). Results are lis-
ted in Table 7. The chemical identities of [18F]8e and [18F]16e
were proven by HPLC on the above-mentioned gradient system
providing coelution of [18F]8e and [18F]16e and their non-
radioactive counterparts 8e and 16e, respectively, which were
added to the injection solutions beforehand.
Under microwave irradiation at 45 °C, the reaction time and
the equivalents of Olah’s reagent could be reduced to 40 min and
1.1 equiv (see Table 6).
Radiosynthesis of Py 9H[18F]F. To prepare Py 9H[18F]F, no-
3
3
carrier-added aqueous [18F]fluoride ions were produced by
irradiation of a 1.2 mL water target using 10 MeV proton beams
on 97.0% enriched [18O]water by the 18O(p,n)18F nuclear reac-
tion. After discharging the cyclotron target an aliquot of aqu-
eous [18F]fluoride ions (194-491 MBq) was used for the
Acknowledgment. These investigations were supported by
the Deutsche Forschungsgemeinschaft (DFG), Collabora-
tive Research Center (Sonderforschungsbereich) 656 “Mole-
cular Cardiovascular Imaging” Projects A3, B1), University
€
of Munster, Germany and by Siemens Medical Solutions to
the European Institute for Molecular Imaging (EIMI) at the
preparation of Py 9H[18F]F. It was transferred in a polypropy-
lene, tube and the water was carefully distilled off in vacuo at
3
120 °C. Then Py 9HF (2.5-10.0 μL, 2.8-11.0 mg, 96-385 μmol
3
HF, 4-16 equiv) and 50-100 μL of CH2Cl2 were added, and the
mixture was heated to 35 °C for 30 min in an ultrasound bath.
The solution was used for the next step without further purification.
Radiosynthesis of 1,1-[18F]Difluoro-11-N-phthalimidylundecane
€
University of Munster, Germany.
Supporting Information Available: General experimental
conditions, spectroscopic data of compounds 5, 6, 8d, 18b, 19b,
g, and 1H, 13C, and 19F NMR spectra for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(16e). The Py 9H[18F]F solution was transferred to a tube
3
containing 4-chlorophenyl-(1-fluoro-11-N-phthalimidylundec-
1-yl)thioether (8e) (11.5 mg, 25 μmol), and CH2Cl2 (50-100 μL)
J. Org. Chem. Vol. 75, No. 18, 2010 6095