A clean and efficient synthesis of 5-(2′-fluoro-2′,3′-dimethylbutan-3′-yl) substituted 1,2,4-oxadiazoles using silver tetrafluoroborate as a fluorodesulfurization reagent

Article abstract of DOI:10.1016/S0022-1139(00)00313-4

5-Ethylthio-6,6,7,7-tetramethyl substituted 4-oxa-1,3-diazabicyclo[3.2.0]hept-2-enes undergo fluorodesulfurization with silver tetrafluoroborate to furnish high yields of 5-(2′-fluoro-2′,3′-dimethylbutan-3′-yl) substituted 1,2,4-oxadiazoles. Ethylthio substituted 1,2,4-triaza- and 1,3-diaza-bicyclo[3.2.0]hept-2-enes behave in a similar fashion to yield 5-(2′-fluoro-2′,3′-dimethylbutan-3′-yl) substituted 1,2,4-triazoles and imidazoles, respectively.

Full text of DOI:10.1016/S0022-1139(00)00313-4

Journal of Fluorine Chemistry 106 (2000) 83±86
0
0
0
0
A clean and ef®cient synthesis of 5-(2 -¯uoro-2 ,3 -dimethylbutan-3 -yl)
substituted 1,2,4-oxadiazoles using silver tetra¯uoroborate
as a ¯uorodesulfurization reagent
a,*
Karl Hemming , Dexter T. Morgan , Robert K. Smalley
Department of Physical Sciences, Clean Technology Research Group, Division of Chemistry, University of Hertfordshire, Hat®eld, AL10 9AB, UK
b
Department of Pure and Applied Chemistry, University of Salford, Salford, M5 4WT, UK
a
b
a
Received 14 April 2000; accepted 18 May 2000
Abstract
-Ethylthio-6,6,7,7-tetramethyl substituted 4-oxa-1,3-diazabicyclo[3.2.0]hept-2-enes undergo ¯uorodesulfurization with silver tetra-
5
uoroborate to furnish high yields of 5-(2 -¯uoro-2 ,3 -dimethylbutan-3 -yl) substituted 1,2,4-oxadiazoles. Ethylthio substituted 1,2,4-
0 0 0 0
¯
triaza- and 1,3-diaza-bicyclo[3.2.0]hept-2-enes behave in a similar fashion to yield 5-(2 -¯uoro-2 ,3 -dimethylbutan-3 -yl) substituted 1,2,4-
0
0
0
0
triazoles and imidazoles, respectively. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Fluoroalkyl substituted heterocycles; Silver tetra¯uoroborate; 1,2,4-Oxadiazoles; 1,2,4-Triazoles; Fluorodesulfurization
1
. Introduction
interest as targets for synthetic and medicinal chemists
8,9,12,14±18] (for a review of the chemistry, synthesis
and applications of 1,2,4-oxadiazoles, see [15]).
[
The search for routes to ¯uorinated organic molecules
which involve milder, less hazardous and more environmen-
tally acceptable alternatives to HF or F based technologies
2
is of continuing importance. Fluorodesulfurization, for
example, is a procedure which often involves either the
use of the reagent I -F [1] or the use of an HF system in the
2. Results and discussion
We have previously reported [19,20] that the 1,3-dipolar
cycloaddition reaction of nitrile imines to the 1-azetine (1)
yields the cycloadducts (2), which on heating undergo loss
2
2
presence of an oxidant [2] such as a N-halo imide [3] or 1,3-
dibromo-5,5-dimethylhydantoin [4]. Recently, it has been
reported that organosulfur compounds can be ¯uorodesul-
furized using cleaner and less hazardous reagents such as
hypervalent iodoarene di¯uorides [5], or AgF [6,7]. These
reports prompt us to report our preliminary results involving
the synthesis of ¯uoroalkyl substituted 1,2,4-oxadiazoles
and other azoles from the ¯uorodesulfurization of ethylthio
substituted diazabicyclo[3.2.0]hept-2-enes using silver tet-
ra¯uoroborate and 2,4,6-collidine. 1,2,4-Oxadiazoles have
attracted much interest in the literature as bioisosteres for
esters and amides [8±10] and exhibit a wide range of
biological activity, for example as dipeptidomimetics
0
0
of EtSH and ring opening to furnish the 5-(2 ,3 -dimethyl-
0
0
buten-1 -en-3 -yl) substituted 1,2,4-triazoles (3), via the
proposed mechanism outlined in Scheme 1. In contrast,
the cycloadducts (4)±(7), obtained from the cycloaddition
of nitrile oxides to the 1-azetine (1), were stable to heat and
did not rearrange [20].
In order to encourage a similar rearrangement of the
adducts (4)±(7), and hence provide access to 1,2,4-oxadia-
zoles, we explored a variety of reagents designed to facilitate
removal of the alkylthio moiety, and therefore, promote
rearrangement. One of the reagent systems that we explored
was the use of silver tetra¯uoroborate and 2,4,6-collidine in
dichloromethane at ice temperature. This system is known
[21] to effect glycoside synthesis by the cyclisation of the
thioacetal (8), as shown in Scheme 2, and depends upon the
removal of the alkylthio moiety by silver, which has a strong
af®nity for sulfur.
[
10], as muscarinic agonists [11], as benzodiazepine recep-
tor antagonists [12] and as antirhinovirals [13]. 1,2,4-Oxa-
diazoles and 1,2,4-triazoles with hydrophobic/lipophilic
¯
uorinated substituents have, therefore, attracted much
*
Corresponding author. Fax: ‡44-1-707-284644.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 3 1 3 - 4

8
4
K. Hemming et al. / Journal of Fluorine Chemistry 106 (2000) 83±86
Scheme 3. Proposed route to the 1,2,4-oxadiazoles (10).
0
dimethylbutan-3 -yl) side chain. The structural assignment
19
was con®rmed by F NMR spectra, each of which revealed
a heptet (Jˆ21±22 Hz) and by low and high resolution mass
spectroscopy, which con®rmed the presence of ¯uorine. The
compounds also gave C, H, N microanalyses consistent with
Scheme 1. 1,3-Dipolar cycloadditions to 1-azetines and the affect of heat
upon the cycloadducts.
0
the assigned structures. Table 1 shows the yields of the 5-(2 -
0
0
0
¯
uoro-2 ,3 -dimethylbutan-3 -yl)-1,2,4-oxadiazoles synthe-
sised.
Presumably (Scheme 5), the product 1,2,4-oxadiazoles
If the mechanistic rationale shown in Scheme 1 is correct,
then this system offered the promise of a silver mediated
desulfurization to generate the intermediate cation (9) which
(11)±(14) are arising as a result of a successful desulfuriza-
tion to furnish the intermediate carbocation (9). Ring open-
ing of the intermediate cation (9) then gives the carbocation
(15), a process driven by the formation of the resonance
stabilised aromatic 1,2,4-oxadiazole ring (for a discussion
concerning the aromatic character of 1,2,4-oxadiazoles, see
[22]). Reaction of this carbocation with a ¯uoride anion
donor would then furnish the ®nal product. Given the excess
of 2,4,6-collidine and silver tetra¯uoroborate which is pre-
sent in our system (see the typical procedure given below), it
is likely that the ¯uoride anion is provided by bis(2,4,6-
0
0
0
should then yield the desired 5-(2 ,3 -dimethylbuten-1 -en-
0
3
-yl) substituted 1,2,4-oxadiazoles (10), as shown in
Scheme 3.
The cycloadducts (4)±(7) were synthesised according to
our published procedure [19,20] and were then treated with
an excess of 2,4,6-collidine and silver tetra¯uoroborate in
dichloromethane at 08C. After 2±3 h, analysis by thin layer
chromatography revealed a clean one spot to one spot
reaction in each case. The new products were easy to isolate
1
by ¯ash silica chromatography. The H NMR spectra and the
mass spectra of the products obtained revealed quickly that
the products did not have the structure of the desired 1,2,4-
oxadiazoles (10). The structures of the products were
Table 1
Fluoroalkyl substituted 1,2,4-Oxadiazoles (11)±(14) from the Cycload-
ducts (4)±(7)
0
0
0
quickly assigned as the 5-(2 -¯uoro-2 ,3 -dimethylbutan-
0
a,b
c
Cycloadduct
1,2,4-Oxadiazole
Yield (%)
3 -yl) substituted 1,2,4-oxadiazoles (11)±(14) shown in
Scheme 4.
(
(
(
(
4), RˆCO
2
Et
(11), RˆCO
2
Et
87
81
74
71
5), RˆPh
(12), RˆPh
Apart from the obvious absence of the vinylic CH proton
2
6), Rˆ4-(OMe)-C
6
H
4
(13), Rˆ4-(OMe)-C
6 4
H
resonances expected for compounds (10), the most diag-
1
nostic signal in each of the H NMR spectra of compounds
7), Rˆ2-(NO
2
)-C
6
H
4
(14), Rˆ2-(NO
Synthesised according to the general procedure.
1 19
All compounds gave satisfactory H NMR, F NMR and high
2 6 4
)-C H
a
(
protons at around 1.4 ppm which was clearly due to the
11)±(14) was a doublet (Jˆ21±22 Hz) integrating as six
b
resolution mass spectra and C, H, N microanalysis.
c
After isolation by flash silica column chromatography.
0
0
0
presence of the ±CF(CH ) moiety of the 5-(2 -¯uoro-2 ,3 -
2
3
Scheme 2. Glycoside synthesis from silver tetrafluoroborate and thioacetal (8).

K. Hemming et al. / Journal of Fluorine Chemistry 106 (2000) 83±86
85
Scheme 4. The synthesis of the fluoroalkyl substituted 1,2,4-oxadiazoles (11)±(14).
Scheme 5. Proposed mechanism for the formation of fluoroalkyl substituted 1,2,4-oxadiazoles (11)±(14).
collidine)silver (1) tetra¯uoroborate (16), the known product
from the reaction of silver (1) tetra¯uoroborate with 2,4,6-
collidine in dichloromethane [23]. The donation of ¯uoride
anion to an electrophile in silver tetra¯uoroborate systems is
well established [23±27]. In particular, the donation of a
2,4,6-collidine under the same conditions as adducts (4)±(7),
0
0
0
0
mixtures of the 5-(2 -¯uoro-2 ,3 -dimethylbutan-3 -yl) sub-
0
0
stituted heterocycles (19) and (21) and the 5-(2 ,3 -dimethyl-
0
0
buten-1 -en-3 -yl) substituted heterocycles (20) and (22)
were obtained (Scheme 6). The pure non-¯uorinated adduct
(20) when treated with silver tetra¯uoroborate and 2,4,6-
collidine in dichloromethane did not yield the ¯uorinated
system (19), indicating that compound (19) does not arise
from the alkene (20).
¯uoride anion to an electrophilic carbon by bis(2,4,6-colli-
dine)silver (1) tetra¯uoroborate has been studied [23,25].
That the carbocation (9) is not scavenging the donated
1
uoride anion is evident from the H NMR and F NMR
19
¯
spectra discussed above.
In conclusion, we have found a mild, clean and ef®cient
¯uorodesulfurization process for ethylthio substituted dia-
zabicyclo[3.2.0]hept-2-enes which allows access to 1,2,4-
When the nitrilimine adduct (17) and the nitrile ylid
adduct (18) were treated with silver tetra¯uoroborate and
2 6 4
Scheme 6. [Arˆ4-(NO )-C H ]: the synthesis of fluoroalkyl substituted 1,2,4-triazoles and imidazoles.

8
6
K. Hemming et al. / Journal of Fluorine Chemistry 106 (2000) 83±86
0
0
0
oxadiazoles and other azoles bearing the 5-(2 -¯uoro-2 ,3 -
0
NH3
carrier
gas),
249.1396,
1
calculated
for
‡
dimethylbutan-3 -yl) structural motif. We are currently
C H N OF‡H 249.1403; H NMR: d 1.38 and 1.45
14 17 2
exploring the behaviour of other alkylthio substituted spe-
cies under these conditions and are also seeking to char-
acterise the nature and scope of the ¯uorodesulfurization
system involved in the current study. We will report the
results of this full and extensive study as a full paper in due
course.
(d, Jˆ22 Hz, 6H, ±CF(CH ) ), 1.5 (s, 6H, 2ÂCH ), 7.45
3
2
3
19
(m, 3H, Ar-H), 8.1 (m, 2H, Ar-H); F NMR: d � 144.26,
� 144.54, � 144.79, � 145.06, � 145.31, � 145.57, � 145.81
(heptet, Jˆ21 Hz, ±CF(CH ) ).
3
2
References
3
. Typical procedure
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1
H NMR spectra were recorded on a Bruker AC-300
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[
[
[
[
[
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(
1
9
vent with trimethylsilane as internal standard. F NMR
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grade and were distilled prior to use.
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bicyclo[3.2.0]hept-2-ene (ꢀ0.5 mmol, 1.0 equivalents) and
dry, freshly distilled 2,4,6-collidine (ꢀ2 mmol, 4.0 equiva-
lents) in dry dichloromethane (10 ml) at 08C, was added
silver tetra¯uoroborate (1.25 mmol, 2.5 equivalents) under
an atmosphere of dry argon. The mixture was stirred at 08C
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4
[
[
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®
ltered and to the ®ltrate was added an equivolume amount
of petroleum ether (60±808). The resultant precipitate of
collidine salts was removed by ®ltration and the ®ltrate was
concentrated by rotary evaporation at 10 mm/Hg to leave a
yellow oil. Puri®cation by ¯ash silica chromatography,
eluting with petroleum ether (60±808)-ethyl acetate mix-
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Scheme 6).
[
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0
0
0
0
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0
0
0
[
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a
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0
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[
[
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1
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(0.140 g). (Found: C, 68.0; H, 6.7; N, 11.4%; C H N OF
14 17 2
requires C, 67.7; H, 6.9; N, 11.3%); exact mass: found (CI,
(