Nucleophile-directed selective transformation of cis-1-tosyl-2- tosyloxymethyl-3-(trifluoromethyl)aziridine into aziridines, azetidines, and benzo-fused dithianes, oxathianes, dioxanes, and (thio)morpholines

Article abstract of DOI:10.1002/chem.201204485

A five-step procedure for the synthesis of cis-1-tosyl-2-tosyloxymethyl-3- (trifluoromethyl)aziridine was developed, starting from 1-ethoxy-2,2,2- trifluoroethanol, involving imination, aziridination, ester reduction, hydrogenation, and N-,O-ditosylation steps. Further synthetic elaborations revealed a remarkable difference in the reactivity of cis-1-tosyl-2- tosyloxymethyl-3-(trifluoromethyl)aziridine with respect to aromatic sulfur and oxygen nucleophiles, thus enabling the selective deployment of this versatile substrate as a building block for the synthesis of functionalized aziridines, azetidines, and benzo-fused dithianes, oxathianes, dioxanes, and (thio)morpholines. Copyright

Full text of DOI:10.1002/chem.201204485

DOI: 10.1002/chem.201204485
Nucleophile-Directed Selective Transformation of cis-1-Tosyl-2-
tosyloxymethyl-3-(trifluoromethyl)aziridine into Aziridines, Azetidines, and
Benzo-Fused Dithianes, Oxathianes, Dioxanes, and (Thio)morpholines
[
a]
[a]
[a, d]
[a]
Sara Kenis, Matthias Dꢀhooghe,* Guido Verniest,
Maaike Reybroeck,
[b]
[
b]
[b]
[c]
Tuyet Anh Dang Thi, Chinh Pham The, Tham Thi Pham, Karl W. Tçrnroos,
[
b]
[a]
Nguyen Van Tuyen,* and Norbert De Kimpe*
Abstract: A five-step procedure for the
synthesis of cis-1-tosyl-2-tosyloxymeth-
yl-3-(trifluoromethyl)aziridine was de-
veloped, starting from 1-ethoxy-2,2,2-
trifluoroethanol, involving imination,
aziridination, ester reduction, hydroge-
nation, and N-,O-ditosylation steps.
Further synthetic elaborations revealed
a remarkable difference in the reactivi-
ty of cis-1-tosyl-2-tosyloxymethyl-3-(tri-
fluoromethyl)aziridine with respect to
aromatic sulfur and oxygen nucleo-
philes, thus enabling the selective de-
ployment of this versatile substrate as a
building block for the synthesis of func-
tionalized aziridines, azetidines, and
benzo-fused dithianes, oxathianes, diox-
anes, and (thio)morpholines.
Keywords: aziridines · heterocycles ·
oxygen · ring expansion · sulfur
Introduction
ACHTUNGTRENNUNG
a
[5]
Due to the inherent reactivity of their constrained ring
system, aziridines have been widely employed as valuable
building blocks in the synthesis of a large variety of func-
ity) of these systems. As a result, CF -substituted com-
3
pounds are increasingly applied in the pharmaceutical and
[6]
agrochemical industry.
Herein, we report the preparation of cis-1-tosyl-2-tosyl-
[1]
tionalized cyclic and acyclic amines. The class of 2-(tri-
fluoromethyl)aziridines comprises an appealing—yet under-
explored—subclass of these three-membered ring struc-
AHCTUNGTRENNUNG
[2,3]
tures.
Owing to the specific chemical and physical proper-
ties of fluorine, that is, its high electronegativity and small
[4]
van der Waals radius, the incorporation of a tri ACHNTUGRNENUGf luoro-
[
a] S. Kenis, Prof. Dr. M. Dꢀhooghe, Prof. Dr. G. Verniest, M. Reybroeck,
Prof. Dr. N. De Kimpe
Department of Sustainable Organic Chemistry and
Technology, Faculty of Bioscience Engineering
Ghent University, Coupure Links 653, 9000 Ghent (Belgium)
Fax : (+32)9-264-62-21
E-mail: matthias.dhooghe@UGent.be
norbert.dekimpe@UGent.be
Results and Discussion
[
b] T. A. Dang Thi, C. Pham The, T. Thi Pham, Dr. N. Van Tuyen
Institute of Chemistry
Vietnam Academy of Sciences and Technology
In a first step toward the synthesis of cis-1-tosyl-2-tosyloxy-
1
8 Hoang Quoc Viet, Cau giay, Hanoi (Vietnam)
methyl-3-(trifluoromethyl)aziridine (6), N-benzylimine
2
Fax: (84) 437914648
E-mail: ngvtuyen@hotmail.com
was prepared through the condensation of the commercially
available latent aldehyde 1-ethoxy-2,2,2-trifluoroethanol (1)
with benzylamine in toluene under Dean–Stark conditions.
Subsequently, imine 2 was treated with ethyl diazoacetate
[
c] Prof. Dr. K. W. Tçrnroos
Department of Chemistry, University of Bergen
Allꢁgt 41, 5007 Bergen (Norway)
[7]
[
d] Prof. Dr. G. Verniest
under Lewis acid catalysis in Et O, thereby yielding cis-ethyl
2
Current address: Vrije Universiteit Brussel
Faculty of Science and Bio-engineering Sciences
Department of Chemistry
1
6
-benzyl-3-(trifluoromethyl)aziridine-2-carboxylate (3) in
2% yield with excellent diastereoselectivity (d.r.>99:1).
[2g]
The reduction of the ester moiety in aziridine 3 by using
lithium aluminum hydride in THF at room temperature af-
forded cis-1-benzyl-2-hydroxymethyl-3-(trifluoromethyl)azir-
Pleinlaan 2, 1050 Brussels (Belgium)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204485.
5966
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 5966 – 5971

FULL PAPER
good yields (Scheme 3). It
should be noted that the ring
opening of the aziridines 7 oc-
curred regio- and stereospecifi-
cally at the C2 position, which
corroborates with the literature
data on the ring opening of 2-
[3]
(
trifluoromethyl)aziridines.
In view of the pronounced bio-
logical properties of com-
pounds that contain a function-
[10]
alized propane skeleton, sul-
fonamides 10 might constitute
useful new entities.
Based on the reactivity of
aziridine
sulfur nucleophiles for the syn-
thesis of functionalized aziri-
6 toward aromatic
Scheme 1. Synthesis of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl) ACHTUNGRNENUGa ziridine (6). Ts=4-toluenesulfonyl.
dines, the same nucleophilic
substitution reaction was envisaged with their oxygen ana-
logues. However, by applying the same reaction conditions
[8]
idine (4) in 79% yield. In the next step, the hydrogenolysis
of N-benzylaziridine 4 toward cis-2-hydroxymethyl-3-(tri-
fluoromethyl)aziridine (5) was performed by using palladi-
um hydroxide on carbon under a hydrogen atmosphere
(
2 bar). Finally, cis-1-tosyl-2-tosyloxymethyl-3-(trifluoro-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
methyl)aziridine (6) was obtained in 47% yield through the
ACHTUNGTRENNUNG
treatment of 2-(hydroxymethyl)aziridine 5 with 2.1 equiva-
lents of tosyl chloride in the presence of triethylamine and
4
-(dimethylamino)pyridine (DMAP) in CH Cl (Scheme 1).
As mentioned above, cis-1-tosyl-2-tosyloxymethyl-3-(tri-
2 2
Scheme 2. Reactions of aziridine 6 with arenethiols and phenols.
fluoromethyl)aziridine (6) holds great potential as a new
synthon for the preparation of a variety of nitrogen-contain-
ing target compounds upon selective manipulation of the re-
active sites. Therefore, in the next part of our investigation,
the reactivity profile of functionalized aziridine 6 was ex-
plored toward different types of aromatic nucleophiles. As
expected, the treatment of cis-1-tosyl-2-tosyloxymethyl-3-
(
trifluoromethyl)aziridine (6) with 0.9 equivalents of an are-
nethiol in the presence of potassium carbonate in acetone
yielded cis-1-tosyl-2-arylthiomethyl-3-(trifluoromethyl)-
aziridines 7a,b (47–55% yield; Scheme 2 and Table 1, en-
A
H
U
G
R
N
N
ACHTUNGTRENNUNG
Scheme 3. Synthesis of N-[2,3-bis
(methylbenzene)sulfonamides (10).
ACHTUNGTRENNGNU( arylthio)-1-(trifluoromethyl)propyl]-4-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ACHTUNGTRENNUNG
[9]
tries 1 and 2). A subequimo-
lar amount of arenethiol
Table 1. Reactions of aziridine 6 with arenethiols and phenols.
(
0.9 equiv), as well as low reac-
Entry
Nucleophile
Reaction
Product Yield Entry
[%]
Nucleophile
(ArOH)
Reaction
conditions
Product Yield
[%]
tion temperatures in the case
of aziridine 7b, appeared to be
necessary to prevent ring open-
ing of the initially formed 2-
[
a]
[a]
(ArSH/ArOH) conditions
1
2
A
7a
7b
55
47
5
6
D
8b
8c
73
95
(
arylthiomethyl)aziridine
Indeed, when N-tosylaziridine
was treated with 2.1 equiva-
7.
B
C
C
D
D
D
6
3
4
8a
8b
25
7
8
8d
8e
87
lents of an arenethiol in ace-
tone at reflux in the presence
of potassium carbonate, the
38
56
corresponding N-[2,3-bis
thio)-1-(trifluoromethyl)pro-
pyl]-4-methylbenzenesulfon-
amides (10) were formed in
ACHTUNGTRNENUNG( aryl-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ACHTUNGTRENNUNG
[
(
a] Reaction conditions: A=ArSH (0.9 equiv), K
2 equiv), acetone, RT, 42 h; C=ArOH (1.1 equiv), K
2
CO
3
(2 equiv), acetone, D, 5 h; B=ArSH (0.9 equiv), K
2
CO
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
H
U
G
R
N
N
ACHTUNGTRENNUNG
2
CO (2 equiv), acetone, 908C (pressure vial), 12–20 h;
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
D=ArOH (1.2 equiv), K
2
CO (5 equiv), DMF, D, 4 h.
3
Chem. Eur. J. 2013, 19, 5966 – 5971
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5967

M. Dꢀhooghe, N. Van Tuyen, N. De Kimpe et al.
as for the reaction with thiophenol (treatment with phenol
and potassium carbonate at reflux in acetone), no conver-
sion of aziridine 6 could be obtained and, therefore, the re-
action was performed at elevated temperatures in a pressure
vial. Surprisingly, the reaction of aziridine 6 with 1.1 equiva-
lents of a phenol in the presence of potassium carbonate in
acetone at 908C in a pressure vial did not afford the antici-
sulfur nucleophiles renders this aziridine a promising build-
ing block for the synthesis of different classes of a-CF -sub-
3
stituted compounds, including aziridines 7, azetidines 8, and
sulfonamides 10.
Having confirmed the ability to discriminate between two
reactive sites within 3-CF -aziridine 6 with respect to phe-
3
nols and arenethiols, the next step involved the evaluation
of (thio)phenols that contained an additional nucleophilic
group to effect ring expansion toward heterobicyclic systems
pated
cis-1-tosyl-2-aryloxymethyl-3-(trifluoromethyl)aziri-
dines, although the reaction cleanly provided a single prod-
uct. After detailed spectroscopic analysis, the obtained reac-
tion product was identified as cis-3-aryloxy-1-tosyl-2-(tri-
fluoromethyl)azetidine (8, Scheme 2). It should be noted
that prolonged reaction times (12–20 h) only afforded 90%
conversion and cis-3-aryloxy-1-tosyl-2-(trifluoromethyl)aze-
tidines 8a,b were obtained in rather low yields (25–38%;
Scheme 2 and Table 1, entries 3 and 4). However, the treat-
ment of aziridine 6 with 1.2 equivalents of a phenol and
through
Therefore, cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)-
aziridine (6) was treated with 1.1 equivalents of benzene-
1,2-dithiol in the presence of an excess of K CO in acetone
a
domino ring-opening/cyclization procedure.
AHCTUNGTRENNUNG
2
3
at reflux for 4 h, thus resulting in the formation of the corre-
sponding 2-(1-tosylamino-2,2,2-trifluoroethyl)-2,3-dihydro-
1,4-benzodithiin (12a) in a stereospecific manner (Table 2,
entry 1). Considering the reactivity of substrate 6 toward S
nucleophiles (Scheme 4), the nucleophilic substitution reac-
tion to form aziridine 11 was expected to occur prior to its
ring opening at the C2 position (Scheme 5). The reaction of
aziridine 6 with 2-mercaptophenol, by applying the same
procedure as mentioned above, resulted in the formation of
2-(1-tosylamino-2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzox-
athiin (12b; Table 2, entry 2). In this case, initial ring open-
ing by an oxygen atom could not be excluded, because this
would ultimately lead to the formation of the same reaction
product (12b). In the case of 2-aminoarenethiols, the reac-
tion proceeded more sluggishly and heating at elevated tem-
peratures in a pressure vial appeared to be necessary to
induce full conversion of the starting material toward 2,3-di-
hydro-1,4-benzothiazines (12c,d; Table 2, entries 3 and 4).
When an excess of 2-amino-4-chlorothiophenol (2.4 equiv)
was added to the reaction, the formation of benzothiazine
12d, as well as the ring-opened product of compound 11d,
that is, N-[2,3-bis[(2-amino-4-chlorophenyl)thio]-1-(trifluoro-
methyl)propyl]-4-methylbenzenesulfonamide, was observed
in a 1:1 ratio, again confirming that sulfur nucleophiles
could induce ring opening of the aziridine moiety when
added in excess.
5
equivalents of K CO in DMF at reflux for 4 h afforded
2 3
the corresponding cis-2-CF -azetidines (8b–8e) in signifi-
3
cantly improved yields (56–95%; Table 1, entries 5–8).
From a mechanistic point of view, the unexpected forma-
tion of azetidines 8 can be rationalized by an initial regio-
and stereospecific ring opening of the aziridine ring at the
C2 position by the phenolate anion to produce intermedi-
ates 9 (Scheme 4, pathway b), followed by intramolecular
displacement of the tosylate group to afford cis-2-CF -azeti-
3
dines 8. This selective approach stands in contrast to the
treatment of aziridine 6 with an arenethiol, which leads to
the clean formation of aziridines 7 through direct tosylate
substitution (Scheme 4, pathway a).
The regiospecific ring opening of 1-tosyl-2-(tosyloxy-
ACHTUNGTRENNUNGm ethyl)aziridines by oxygen nucleophiles as an entry to aze-
tidine synthesis is surprising and has not been described in
the literature so far. Moreover, only a few reports on aziri-
dine-to-azetidine ring expansions are known in the litera-
[11]
ture, thus making this ring transformation a rare and pe-
culiar one. In addition, the chemistry of 2-(trifluoromethyl)-
ACHTUNGTRENNUNGa zetidines comprises a scarcely investigated field of re-
AHCTUNGTRENNUNG
[12]
search, both in terms of their synthesis and their reactivi-
ty, thus pointing to the significant value of this new
approach toward azetidines 8. Furthermore, the remarkable
difference in reactivity of cis-1-tosyl-2-tosyloxymethyl-3-
To validate its regioselective ring opening by oxygen nu-
cleophiles, the reactions of aziridine 6 with a number of phe-
nols that contained an additional nucleophilic group were
(
trifluoromethyl) ACHTUNGTRENNUNGa ziridine (6) toward aromatic oxygen and
Table 2. Reactions of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)-
AHCTUNGTRENNUNG
1
2
3
Entry
X
Y
R
R
R
Reaction
Product Yield [%]
conditions
1
2
3
S
S
S
S
O
NH
H
H
H
H
H
H
H
H
H
D, 4 h
D, 5 h
608C, 48 h
12a
12b
12c
80
49
76
(
pressure vial)
1508C, 16 h
pressure vial)
D, 10 h
D, 9 h
4
S
NH Cl
H
H
H
12d
68
(
5
6
7
8
O
O
O
O
O
O
H
H
H
14a
14b
14c
14d
79
58
55
71
Br Br
Scheme 4. Reaction mechanism for the synthesis of cis-1-tosyl-2-arylthio-
-(trifluoromethyl)aziridines (7) and cis-1-tosyl-3-aryloxy-2-(trifluoro-
ACHTUNGTRENNUNGm ethyl)azetidines (8).
O
NH
H
H
tBu tBu D, 15 h
D, 4 h
3
H
H
5968
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Chem. Eur. J. 2013, 19, 5966 – 5971

Nucleophile-Directed Selective Transformations
FULL PAPER
Scheme 5. Formation of heterobicycles 12 and 14 from cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine (6).
explored. Hence, aziridine 6 was treated with 1.1 equivalents
By means of these examples, the synthetic potential of
cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine (6)
as a new building block was demonstrated, thus revealing a
unique difference in reactivity toward aromatic O and S nu-
cleophiles that allowed for the selective synthesis of a varie-
of different benzene-1,2-diols in the presence of K CO in
2
3
acetone, thereby furnishing 2-(1-tosylamino-2,2,2-trifluoro-
ethyl)-2,3-dihydro-1,4-benzodioxines 14a,b in good yields
Table 2, entries 5 and 6). At this point, no conclusion could
ACHTUNGTRENNUNG
(
be made concerning the regioselectivity of the reaction, due
to the use of symmetric nucleophiles. Therefore, 3,5-di-tert-
butylbenzene-1,2-diol was used, thus resulting in the forma-
tion of 5,7-di-tert-butyl-2-(1-tosylamino-2,2,2-trifluoroethyl)-
ty of CF -substituted aziridines (7), azetidines (8), sulfona-
3
mides (10), and heterobicyclic systems (12 and 14). In view
of the known biological properties of compounds that con-
tain a functionalized azetidine skeleton, azetidines 8 might
[14]
2,3-dihydro-1,4-benzodioxine (14c) in 55% yield (Table 2,
constitute promising structures. Moreover, oxa- and thia-
heterobicyclic systems (12 and 14) represent an interesting
class of compounds because they are known to possess a
broad spectrum of biological activities, such as a-adrenergic
entry 7). According to literature data, the least sterically
hindered oxygen atom in 3,5-di-tert-butyl-1,2-benzenediol
[13]
would react first with the electrophile,
the reactivity of aziridine 6 toward oxygen nucleophiles
Scheme 4), would furnish 1,4-benzodioxine 14c as the re-
sulting structure. Because the reaction outcome could not
which, based on
[
15]
[15d]
[15d]
blocking,
anxiolytic,
hepatoprotective,
antidiabe-
[
15e]
[16]
[17]
(
tic,
antimicrobial, antioxidant, and antiemetic activi-
ty.
In summary, a straightforward synthesis of cis-1-tosyl-2-to-
[18]
1
13
be solely determined by H and C NMR analysis, a single-
crystal X-ray diffraction study was necessary to unambigu-
ously assign the correct structure (see the Supporting Infor-
mation), which was 5,7-di-tert-butyl-2-(1-tosylamino-2,2,2-
trifluoroethyl)-2,3-dihydro-1,4-benzodioxine (14c). In this
way, both the connectivity and the proposed relative stereo-
chemistry within these new bicyclic systems were unequivo-
cally established. Thus, we can conclude that these reactions
proceed in a regio- and stereospecific manner in which the
ring is selectively opened by the oxygen nucleophile at the
syloxymethyl-3-(trifluoromethyl)aziridine has been devel-
oped, starting from commercially available 1-ethoxy-2,2,2-
trifluoroethanol. Moreover, the reactivity profile of this new
a-CF -aziridine toward a number of aromatic nucleophiles
3
was investigated, thus providing a convenient access to func-
tionalized aziridines, azetidines, and biologically relevant
benzo-fused dithianes, oxathianes, dioxanes, and (thio)mor-
pholines. Surprisingly, this study revealed a remarkable dif-
ference between the reactivity of cis-1-tosyl-2-tosyloxymeth-
yl-3-(trifluoromethyl)aziridine toward aromatic sulfur and
oxygen nucleophiles. Whereas sulfur nucleophiles selectively
attacked the exocyclic methylene carbon atom, thereby re-
sulting in the direct displacement of the tosylate group,
C2 position through an S 2-type approach (Scheme 5). Fi-
N
nally, also, 2-aminophenol was used as a nucleophile, thus
affording 2-(1-tosylamino-2,2,2-trifluoroethyl)-2,3-dihydro-
1,4-2H-benzoxazine (14d) in 71% yield (Table 2, entry 8).
Chem. Eur. J. 2013, 19, 5966 – 5971
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5969

M. Dꢀhooghe, N. Van Tuyen, N. De Kimpe et al.
À1
+
oxygen nucleophiles induced ring opening of the three-
membered ring in a regio- and stereospecific manner at the
C2 position.
686, 676 cm ; MS (70 eV): m/z (%): 388 (55) [M+H] , 337 (100);
+
HRMS (ES-TOF): m/z calcd for C17
found: 388.0651.
17 3 2 2
H F NO S : 388.0653 [M+H] ;
Synthesis of cis-3-phenoxy-1-tosyl-2-(trifluoromethyl)azetidine (8b): To a
solution of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine (6,
5
0 mg, 0.11 mmol) in dry DMF (5 mL) were added potassium carbonate
76 mg, 0.55 mmol) and phenol (12 mg, 0.13 mmol). After heating the re-
action mixture at reflux for 4 h, water was added (10 mL) and the result-
ing mixture was extracted with CH Cl (3ꢃ5 mL). Afterwards, the com-
bined organic phases were washed with a 10% aqueous solution of HCl
(
Experimental Section
2
2
Synthesis of cis-2-hydroxymethyl-3-(trifluoromethyl)aziridine (5): To a
[
8]
solution of cis-1-benzyl-2-hydroxymethyl-3-(trifluoromethyl)aziridine 4
1 g, 4.33 mmol) in CH Cl (15 mL) was added Pd(OH) /C (20% mass
fraction, 176 mg, 0.87 mmol). The mixture was stirred at RT for 64 h
under a H atmosphere (2 bar) and subsequently filtered through a short
pad of Celite. The pad was washed exhaustively with CH Cl (5ꢃ10 mL)
and the collected organic fractions were evaporated under reduced pres-
sure. Recrystallization from CH Cl afforded pure cis-2-hydroxymethyl-3-
trifluoromethyl)aziridine (5). M.p. 60–618C; recrystallized from CH Cl
, 258C, TMS): d=1.38 (br s, 1H), 2.09 (t, J=
.5 Hz, 1H), 2.60–2.68 (m, 1H), 2.74–2.86 (m, 1H), 3.68–3.85 ppm (m,
(
3ꢃ5 mL) and a 10% aqueous solution of NaHCO
3
(3ꢃ5 mL). Drying
(
2
2
2
(
NaSO ), filtration of the drying agent, and evaporation of the solvent
4
yielded cis-3-phenoxy-1-tosyl-2-(trifluoromethyl)aziridine (8a), which
2
was purified by column chromatography on silica gel (n-hexane/EtOAc,
1
2
2
9
2:8). M.p. 115–1168C; R
f
=0.15 (petroleum ether/EtOAc, 9:1); H NMR
(
300 MHz, CDCl
3
, 258C, TMS): d=2.46 (s, 3H), 4.10 (dd, J=9.7, 6.0 Hz,
2
2
1
5
2
H), 4.46 (dd, J=9.7, 8.0 Hz, 1H), 4.82 (dq, J=7.3, 7.3 Hz, 1H), 5.07–
(
2
2
;
.11 (m, 1H), 6.74–6.75 (m, 1H), 7.01 (~t, J=7.4 Hz, 1H), 7.27–7.29 (m,
1
H NMR (300 MHz, CDCl
3
13
H), 7.36 (d, J=8.2 Hz, 2H), 7.79 ppm (d, J=8.2 Hz, 2H); C NMR
5
2
(
3
125 MHz, CDCl
3.0 Hz, CHCF
3
3
, 258C): d=21.7 (CH
), 65.4 (CH), 115.0 (2ꢃCH), 122.6 (CH), 123.0 (q,
), 128.0 (2ꢃCH), 129.8 (2ꢃCH), 129.9 (2ꢃCH),
3 2
), 57.2 (CH ), 64.6 (q, J ACHTUNGTRENNUNG( C,F)=
1
3
H); C NMR (75 MHz, CDCl
3
, 258C): d=34.0 (q, J
ACHTUNGTRENNUNG
CHCF
3
), 36.7 (CH), 60.7 (CH ), 124.7 ppm (q, J
2
A
H
U
G
E
N
N
3
J(C,F)=285.8 Hz, CF
34.2 (C), 144.8 (C), 156.4 ppm (C); F NMR (282 MHz, CDCl
(H,F)=7.9 Hz); IR (ATR): n˜ =2930, 1598, 1495,
3
1
9
F NMR (282 MHz, CDCl
IR (ATR): n˜ =3281, 3249 cm (NH, OH); MS (70 eV): m/z (%): 142
3
, 258C): d=À65.36 ppm (d, J
A
H
N
T
E
N
N
19
1
3
, 258C):
À1
d=À71.24 ppm (3F, d, J
ACHTUNGTRENNUNG
+
(
[
100) [M+H] ; HRMS (ES-TOF): m/z calcd for C
M+H] ; found: 142.0476.
4
H
7
F
3
NO: 142.0480
À1
1
3
3
358, 1250, 1155, 1101, 1029, 813, 689, 473 cm ; MS (70 eV): m/z (%):
+
+
72 (100) [M+H] ; HRMS (ES-TOF): m/z calcd for C17
17 3 3
H F NO S:
Synthesis of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine (6):
To a solution of cis-2-hydroxymethyl-3-(trifluoromethyl)aziridine 5 (1 g,
+
72.0881 [M+H] ; found: 372.0847.
Synthesis of N-[2,3-bis(phenylthio)-1-(trifluoromethyl)propyl]-4-methyl-
benzenesulfonamide (10a): To a solution of cis-1-tosyl-2-tosyloxymethyl-
7
1
(
.09 mmol) in CH
2
Cl
2
3
(50 mL) at RT were added Et N (1.43 g,
4.18 mmol), TsCl (2.84 g, 14.89 mmol), and 4-dimethylaminopyridine
3
-(trifluoromethyl)aziridine (6, 90 mg, 0.20 mmol) in acetone (4 mL)
were added benzenethiol (46 mg, 0.42 mmol) and potassium carbonate
83 mg, 0.60 mmol). After stirring for 4 h at reflux, the reaction mixture
was neutralized by using a saturated aqueous solution of NaHCO
(5 mL), poured in water (10 mL), and extracted with EtOAc (3ꢃ5 mL).
Drying (MgSO ), filtration of the drying agent, and evaporation of the
173 mg, 1.42 mmol). After heating the reaction mixture at reflux for 4 h,
the solvent was evaporated in vacuo to afford the crude product. Recrys-
tallization from CH Cl afforded an analytically pure sample of cis-1-
tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine (6). M.p. 64–658C; re-
(
2
2
3
1
crystallized from CH
.45 (s, 3H), 2.47 (s, 3H), 3.26–3.40 (m, 2H), 4.07–4.19 (m, 2H), 7.34 (d,
J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H),
2 2 3
Cl ; H NMR (300 MHz, CDCl , 258C, TMS): d=
4
2
solvent under reduced pressure afforded N-[2,3-bis(phenylthio)-1-(tri-
fluoromethyl)propyl]-4-methylbenzenesulfonamide (10a), which was pu-
1
3
7
.80 ppm (d, J=8.3 Hz, 2H); C NMR (75 MHz, CDCl
d=21.7 (CH ), 21.8 (CH ), 39.7 (q, J(C,F)=41.6 Hz, CHCF
5.0 (d, J=2.3 Hz, CH ), 122.1 (q, J(C,F)=275.4 Hz, CF
CH), 128.4 (2ꢃCH), 130.0 (2ꢃCH), 130.1 (2ꢃCH), 132.0 (C), 132.8 (C),
3
, 258C, TMS):
), 39.9 (CH),
), 128.0 (2ꢃ
rified by preparative TLC on silica gel (petroleum ether/EtOAc, 95:5).
3
3
A
H
U
G
R
N
U
G
3
1
M.p. 124–1258C;
300 MHz, CDCl
12.4 Hz, 1H), 3.20–3.25 (m, 2H), 4.73–4.80 (m, 1H), 5.52 (br s, 1H),
.11–7.28 (m, 10H), 7.30 (d, J=8.3 Hz, 2H), 7.79 ppm (d, J=8.3 Hz,
R
f
=0.15 (petroleum ether/EtOAc, 9:1); H NMR
6
2
A
H
U
G
R
N
U
G
3
(
3
, 258C, TMS): d=2.43 (s, 3H), 2.92 (dd, J=14.6,
1
9
1
45.5 (C), 146.1 ppm (C); F NMR (282 MHz, CDCl
3
, 258C): d=
7
À65.81 ppm (d, J(H,F)=6.6 Hz); IR (ATR): n˜ =1364, 1338, 1290, 1166,
ACHTUNGTRENNUNG
1
3
À1
2H); C NMR (75 MHz, CDCl ), 37.2
3
, 258C, TMS): d=21.6 (CH
3
1
148, 1091, 984, 879, 740, 678, 666 cm ; MS (70 eV): m/z (%): 467 (100)
+
(CH ), 48.0 (CH), 54.8 (q, J(C,F)=31.5 Hz, CHCF ), 124.2 (q, J ACHTUNGTRENNUNG( C,F)=
A
H
U
G
R
N
N
2
3
[
[
M+NH
M+NH
4
] ; HRMS (ES-TOF): m/z calcd for C18
H
22
F
3
N
2
O
5
S
2
: 467.0922
+
283.0 Hz, CF ), 127.2 (3ꢃCH), 128.3 (CH), 129.2 (2ꢃCH), 129.3 (2ꢃ
] ; found: 467.0923.
3
4
CH), 129.8 (2ꢃCH), 130.7 (2ꢃCH), 132.2 (C), 132.8 (2ꢃCH), 133.6 (C),
Synthesis of cis-2-phenylthiomethyl-1-tosyl-3-(trifluoromethyl)aziridine
7a): To a solution of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)azir-
idine (6, 90 mg, 0.20 mmol) in acetone (4 mL) were added benzenethiol
20 mg, 0.18 mmol) and potassium carbonate (55 mg, 0.40 mmol). After
stirring the reaction mixture for 5 h at reflux, the reaction mixture was
neutralized by using a saturated aqueous solution of NaHCO (5 mL).
Afterwards, the resulting reaction mixture was poured in water (10 mL)
and extracted with EtOAc (3ꢃ5 mL). Drying (MgSO ), filtration of the
1
9
1
3
37.4 (C), 144.0 ppm (C); F NMR (282 MHz, CDCl , 258C): d=
(
À1
À71.83 ppm (3F, d, J
ACHTUNGTRENNUNG( H,F)=6.6 Hz); IR (ATR): n˜ =3240 cm (NH); MS
À
(
C
70 eV): m/z (%): 496 (100) [MÀH] ; HRMS (ES-TOF): m/z calcd for
(
À
23
H
21
F
3
NO
2
S
3
: 496.0687 [MÀH] ; found: 496.0694.
Synthesis of oxaheterobicyclic (12) and thiaheterobicyclic systems (14):
As a representative example, the synthesis of 2-(1-tosylamino-2,2,2-tri-
fluoroethyl)-2,3-dihydro-1,4-benzodithiin (12a) is described. To a solution
of cis-1-tosyl-2-tosyloxymethyl-3-(trifluoromethyl)aziridine (6, 100 mg,
3
4
drying agent, and evaporation of the solvent in vacuo yielded cis-2-phe-
nylthiomethyl-1-tosyl-3-(trifluoromethyl)aziridine (7a), which was puri-
fied by means of preparative TLC on silica gel (petroleum ether/EtOAc,
0
.22 mmol) in acetone (5 mL) were added benzene-1,2-dithiol (26 mg,
0.24 mmol) and potassium carbonate (61 mg, 0.44 mmol). After stirring
for 4 h at reflux, the reaction mixture was poured in water (10 mL) and
9
5:5). These reaction conditions only resulted in 64% conversion of aziri-
dine 6. However, these conditions appeared to be necessary to avoid ring
4
extracted with EtOAc (3ꢃ5 mL). Drying (MgSO ), filtration of the
opening of the prepared aziridine (7a) by benzenethiol. M.p. 67–688C;
drying agent, and evaporation of the solvent yielded 2-(1-tosylamino-
2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzodithiin (12a), which was puri-
fied by column chromatography on silica gel (n-hexane/EtOAc, 92:8) to
obtain an analytically pure sample. In the syntheses of 3-(1-tosylamino-
2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzothiazines (12c,d), the reactions
were performed in a pressure vial at 608C for 48 h and at 1508C for 16 h,
1
R
f
=0.14 (petroleum ether/EtOAc, 95:5); H NMR (300 MHz, CDCl
3
,
2
58C, TMS): d=2.44 (s, 3H), 3.10–3.13 (m, 2H), 3.16–3.23 (m, 1H), 3.29
(
dq, J=6.1, 6.1 Hz, 1H), 7.21–7.36 (m, 7H), 7.79 ppm (d, J=8.2 Hz, 2H);
1
3
C NMR (75 MHz, CDCl
J(H,F)=41.2 Hz, CHCF ), 42.5 (CH
27.2 (CH), 128.3 (2ꢃCH), 129.2 (2ꢃCH), 129.9 (2ꢃCH), 130.4 (2ꢃ
3
, 258C): d=21.7 (CH
3
), 31.1 (CH), 41.1 (q,
3
2
), 122.8 (q, J
A
H
U
G
R
N
U
3
1
respectively. M.p. 131–1328C;
R
f
=0.27 (n-hexane/EtOAc, 85:15);
1
9
1
CH), 133.2 (C), 134.0 (C), 145.6 ppm (C); F NMR (282 MHz, CDCl
3
,
H NMR (500 MHz, CDCl , 258C, TMS): d=2.41 (s, 3H), 2.63 (dd, J=
3
2
58C): d=À65.18 ppm (3F, d, J
A
H
U
G
R
N
N
(H,F)=6.6 Hz); IR (ATR): n˜ =3043,
13.7, 10.6 Hz, 1H), 3.20 (dd, J=13.7, 4.9 Hz, 1H), 4.23–4.30 (m, 2H),
5.65 (d, J=9.6 Hz, 1H), 7.13–7.16 (m, 2H), 7.22 (d, J=8.2 Hz, 2H), 7.28–
1
447, 1334, 1283, 1241, 1162, 1140, 1126, 1088, 1014, 886, 828, 819, 723,
5970
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 5966 – 5971

Nucleophile-Directed Selective Transformations
FULL PAPER
1
3
7
2
3
(
1
.34 (m, 2H), 7.67 ppm (d, J=8.2 Hz, 2H); C NMR (125 MHz, CDCl
58C, TMS): d=21.6 (CH ), 32.8 (CH ), 47.0 (CH), 57.3 (q, J(C,F)=
0.7 Hz, CHCF ), 123.8 (q, J(C,F)=283.8 Hz, CF ), 126.2 (CH), 126.9
3
,
[6] a) G. Sandford, Philos. Trans. R. Soc. London, Ser. A 2000, 358, 455;
b) B. Deng, F. Yang, J. Fan, H. Feng, Y. Wang, T. Yang, PCT Int.
Appl., 2009, WO 2009082881; c) V. De Matteis, F. L. van Delft, H.
Jakobi, S. Lindell, J. Tiebes, F. P. J. T. Rutjes, J. Org. Chem. 2006, 71,
7527, and the references therein.
3
2
ACHTUNGTRENNUNG
3
A
H
U
G
R
N
U
3
2ꢃCH), 127.0 (CH), 129.2 (CH), 129.7 (2ꢃCH), 130.2 (CH), 132.0 (C),
32.8 (C), 145.5 (C), 146.1 ppm (C); IR (ATR): n˜ =3270 cm (NH); MS
À1
À
(
C
70 eV): m/z (%): 418 (100) [MÀH] ; HRMS (ES-TOF): m/z calcd for
[7] T. Ono, V. P. Kukhar, V. A. Soloshonok, J. Org. Chem. 1996, 61,
6563.
+
17
H
17
F
3
NO
5
S
3
: 420.0374 [M+H] ; found: 420.03734.
[
8] P. Davoli, A. Forni, I. Moretti, F. Prati, G. Torre, Tetrahedron 2001,
57, 1801.
9] M. Karikomi, M. Dꢀhooghe, G. Verniest, N. De Kimpe, Org.
Biomol. Chem. 2008, 6, 1902.
2
-(1-Tosylamino-2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzodioxine (14a):
1
M.p. 142–1438C; R
CDCl , 258C, TMS): d=2.44 (s, 3H), 4.06 (dd, J=11.6, 9.4 Hz, 1H), 4.17
dq, J=8.0, 8.0 Hz, 1H), 4.29 (dd, J=11.6, 2.2 Hz, 1H), 4.51 (d, J=
f
=0.19 (n-hexane/EtOAc, 98:2); H NMR (500 MHz,
[
3
(
[
10] a) M. Dꢀhooghe, A. Waterinckx, T. Vanlangendonck, N. De Kimpe,
9
2
.2 Hz, 1H), 5.46 (d, J=9.7 Hz, 1H), 6.86–6.88 (m, 2H), 6.89–6.90 (m,
1
3
Tetrahedron 2006, 62, 2295; b) J. Teerlink, B. Massie, Am. J. Cardiol.
H), 7.31 (d, J=8.2 Hz, 2H), 7.75 ppm (d, J=8.2 Hz, 2H); C NMR
258C): d=21.6 (CH ), 54.6 (q, (C,F)=30.7 Hz,
), 69.1 (CH), 117.4 (CH), 117.4 (CH), 121.9 (CH),
(C,F)=283.2 Hz, CF ), 127.0 (2ꢃCH), 129.8 (2ꢃ
CH), 137.4 (C), 142.1 (C), 142.7 (C), 144.2 ppm (C); IR (ATR): n˜ =
1
999, 84, 94; c) K. W. Bair, R. L. Tuttle, V. C. Knick, M. Cory, D. D.
(
125 MHz, CDCl
3
,
3
JACHTUNGTRENNUNG
McKee, J. Med. Chem. 1990, 33, 2385; d) F. A. Davis, P. Zhou, Tetra-
hedron Lett. 1994, 35, 7525; e) D. P. Schumacher, J. E. Clarck, B. L.
Murphy, P. A. Fischer, J. Org. Chem. 1990, 55, 5291.
3 2
CHCF ), 65.2 (CH
1
22.5 (CH), 123.6 (q, J
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
À1
À
[11] a) S. Stankovi c´ , H. Goossens, S. Catak, M. Tezcan, M. Waroquier, V.
3
256 cm (NH); MS (70 eV): m/z (%): 386 (100) [MÀH] ; HRMS (ES-
+
Van Speybroeck, M. Dꢀhooghe, N. De Kimpe, J. Org. Chem. 2012,
TOF): m/z calcd for C17
H
17
F
3
NO
4
S: 388.0830 [M+H] ; found: 388.0830.
7
7, 3181; b) S. Stankovi c´ , S. Catak, M. Dꢀhooghe, H. Goossens, K.
Abbaspour Tehrani, P. Bogaert, M. Waroquier, V. Van Speybroeck,
N. De Kimpe, J. Org. Chem. 2011, 76, 2157; c) S. Mangelinckx, A.
ˇ
ˇ
Zukauskait e˙ , V. Buinauskait e˙ , A. Sa cˇ kus, N. De Kimpe, Tetrahedron
Lett. 2008, 49, 6896; d) V. R. Gaertner, J. Org. Chem. 1970, 35, 3952;
e) J. Deyrup, C. L. Moyer, Tetrahedron Lett. 1968, 9, 6179.
Acknowledgements
The authors are indebted to Ghent University, FWO-Vlaanderen (Re-
search Foundation-Flanders), the Vietnamese National Foundation for
Science and Technology Development (NAFOSTED), and to Janssen
Research and Development, a Division of Janssen Pharmaceutica NV,
for financial support.
[12] a) S. Kenis, M. Dꢀhooghe, G. Verniest, T. A. Dang Thi, C. P. The,
T. V. Nguyen, N. De Kimpe, J. Org. Chem. 2012, 77, 5982; b) J.
Jiang, H. Shah, R. J. DeVita, Org. Lett. 2003, 5, 4101; c) S. V. Moi-
seev, V. M. Goncharov, G. V. Zatonsky, V. F. Cherstkov, N. V.
Vasil’ev, Mendeleev Commun. 2006, 16, 184; d) T. Shimada, A.
Ando, T. Takagi, M. Koyama, T. Miki, I. Kumadaki, Chem. Pharm.
Bull. 1992, 40, 1665; e) N. Katagiri, H. Watanabe, C. Kaneko, Chem.
Pharm. Bull. 1988, 36, 3354.
[13] a) M. Barbier, D. H. R. Barton, M. Devys, R. S. Tophi, Tetrahedron
1987, 43, 5031; b) L. G. Tietze, K. F. Wilckens, S. Yilmaz, F. Stecker,
J. Zinngrebe, Heterocycles 2006, 70, 309; c) L. A. Maslovskaya, A. I.
Savchenko, Russ. J. Gen. Chem. 2003, 73, 394.
[
1] a) D. Tanner, Angew. Chem. 1994, 106, 625; Angew. Chem. Int. Ed.
Engl. 1994, 33, 599; b) H. M. I. Osborn, J. Sweeney, Tetrahedron:
Asymmetry 1997, 8, 1693; c) J. B. Sweeney, Chem. Soc. Rev. 2002, 31,
2
1
47; d) G. S. Singh, M. Dꢀhooghe, N. De Kimpe, Chem. Rev. 2007,
07, 2080; e) S. Stankovi c´ , M. Dꢀhooghe, S. Catak, H. Eum, M. War-
oquier, V. Van Speybroeck, N. De Kimpe, H.-J. Ha, Chem. Soc. Rev.
012, 41, 643.
[14] a) D. E. Nichols, S. Frescas, D. Marona-Lewicka, D. M. Kurrasch-Or-
baugh, J. Med. Chem. 2002, 45, 4344; b) C. G. Bonde, A. Peepliwal,
N. J. Gaikwad, Arch. Pharm. Chem. Life Sci. 2010, 343, 228; c) T.
Isoda, I. Yamamura, S. Tamai, T. Kumagai, Y. Nagao, Chem. Pharm.
Bull. 2006, 54, 1408; d) D. Ferraris, S. Belyakov, W. Li, E. Oliver, Y.-
S. Ko, D. Calvin, S. Lautar, B. Thomas, C. Rojas, Curr. Top. Med.
Chem. 2007, 7, 597.
[15] a) R. Barbaro, L. Betti, M. Botta, F. Corelli, G. Giannaccini, L. Mac-
cari, F. Manetti, G. Strappaghetti, S. Corsano, Bioorg. Med. Chem.
2002, 10, 361; b) M. L. Bolognesi, R. Budriesi, A. Cavalli, A. Chia-
2
[
2] a) F. Grellepois, J. Nonnenmacher, F. Lachaud, C. Portella, Org.
Biomol. Chem. 2011, 9, 1160; b) Y. Yamauchi, T. Kawate, H. Itaha-
shi, T. Katagiri, K. Uneyama, Tetrahedron Lett. 2003, 44, 6319; c) S.
Kenis, M. Dꢀhooghe, G. Verniest, V. D. Nguyen, T. A. Dang Thi,
T. V. Nguyen, N. De Kimpe, Org. Biomol. Chem. 2011, 9, 7217; d) T.
Katagiri, H. Ikhara, M. Takahashi, S. Kashino, K. Furuhashi, K. Un-
eyama, Tetrahedron: Asymmetry 1997, 8, 2933; e) R. Maeda, K.
Ooyama, R. Anno, M. Shiosaki, T. Azema, T. Hanamoto, Org. Lett.
2
010, 12, 2548; f) K. Higashiyama, M. Matsumura, A. Shiogama, T.
ACHTUNGERTNNUNGr ini, R. Gotti, A. Leonardi, A. Minarini, E. Poggesi, M. Recanatini,
Yamauchi, S. Ohmiya, Heterocycles 2002, 58, 85; g) B. Crousse, S.
Narizuka, D. Bonnet-Delphon, J.-P. Bꢁguꢁ, Synlett 2001, 679; h) T.
Akiyama, S. Ogi, K. Fuchibe, Tetrahedron Lett. 2003, 44, 4011.
3] a) T. Katagiri, M. Takahashi, Y. Fujiwara, H. Ihara, K. Uneyama, J.
Org. Chem. 1999, 64, 7323; b) N. M. Karimova, Y. L. Teplenicheva,
A. F. Kolomiets, A. V. Fokin, Russ. Chem. Bull. 1997, 46, 1136; c) T.
Katagiri, Y. Katayama, M. Taeda, T. Ohshima, N. Iguchi, K. Uneya-
ma, J. Org. Chem. 2011, 76, 9305; d) G. Rinaudo, S. Narizuka, N.
Askari, B. Crousse, D. Bonnet-Delphon, Tetrahedron Lett. 2006, 47,
M. Rosini, V. Tumiatti, C. Melchiorre, J. Med. Chem. 1999, 42, 4214;
c) W. Quaglia, M. Pigini, A. Piergentili, M. Giannella, G. Marucci,
E. Poggesi, A. Leonardi, C. Melchiorre, J. Med. Chem. 1999, 42,
2961; d) K. Kꢅnya, R. Ferenczi, A. Czompa, A. Kiss-Szikszai, T.
Kurtꢆn, S. Antus, ARKIVOC 2008, 3, 200 and the references there-
[
ˇ
ˇ
in; e) J. IIaS, P. S. Anderluh, M. S. Dolenc, D. Kikelj, Tetrahedron
2005, 61, 7325 and the references therein.
[16] a) D. Armenise, M. Muraglia, M. A. Florio, N. De Laurentis, A.
Rosato, A. Carrieri, F. Corbo, C. Franchini, Arch. Pharm. 2012, 345,
407; b) F. Schiaffella, A. Macchiarulo, L. Milanese, A. Vecchierelli,
G. Costantino, D. Pietrella, R. Fringuelli, J. Med. Chem. 2005, 48,
7658.
[17] a) P. Hoelscher, R. Jautelat, H. Rehwinkel, S. Jaroch, S. Suelzle, M.
Hillmann, G. A. Burton, F. M. McDonald, PCT Int. Appl., 2001,
WO0181324; b) S. Menichetti, M. C. Aversa, F. Cimino, A. Contini,
C. Viglianisi, A. Tomaino, Org. Biomol. Chem. 2005, 3, 3066.
[18] T. Kuroita, M. Sakamori, T. Kawakita, Chem. Pharm. Bull. 1996, 44,
756.
2
065; e) R. Maeda, R. Ishibashi, R. Kamaishi, K. Hirotaki, H.
Furuno, T. Hanamoto, Org. Lett. 2011, 13, 6240.
[
[
4] a) W. R. Dolbier, J. Fluorine Chem. 2005, 126, 157; b) Bioorganic
and Medicinal Chemistry of Fluorine (Eds.: J.-P. Bꢁguꢁ, D. Bonnet-
Delpon), John Wiley & Sons, Hoboken, 2008; c) K. Mꢄller, C. Faeh,
F. Diederich, Science 2007, 317, 1881; d) B. E. Smart, J. Fluorine
Chem. 2001, 109, 3; e) D. OꢀHagan, Chem. Soc. Rev. 2008, 37, 308.
5] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320; b) W. K. Hagmann, J. Med. Chem. 2008, 51,
4
359; c) H.-J. Bçhm, D. Banner, S. Bendels, M. Kansky, B. Kuhn, K.
Received: December 17, 2012
Mꢄller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637.
Published online: March 19, 2013
Chem. Eur. J. 2013, 19, 5966 – 5971
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5971