1876
G.W. Bluck et al. / Journal of Fluorine Chemistry 125 (2004) 1873–1877
the major isolable product (15) (14% yield) after preparative
HPLC. The position of fluorine incorporation into (14) was
determined by nOe and HMBC NMR experiments and a
Borodkin [15] in order to determine which isomers
were formed. Integration of these signals gave a rough
quantification of the new products. Absolute quantifi-
cation of the materials in the reaction mixture was
achieved by integration of the GC trace, comparison
1
consideration of fluorine couplings in the H NMR spectra.
1
9
with the F NMR integration data and calculation
against the standard added to the sample.
3
. Conclusions
We have shown that microwave conditions are readily
applicable to the fluorination of aromatic molecules, when a
suitable electrophilic fluorination agent is used such as
4
.3. General procedure for microwave fluorination
1
To a 5 mL microwave tube, charged with Selectfluor
178 mg, 0.5 mmol) was added substrate (0.5 mmol). Acet-
1
1
Selectfluor (1) or Accufluor (2). It has been further
demonstrated that it is possible to use these conditions to
rapidly fluorinate quite complex molecules and isolate novel
products in useful quantities.
(
onitrile (2.5 mL) was added and the tube capped. The
reaction was then irradiated to heat it to 150 8C in the
microwave cavity for the appropriate length of time. The
readings from the temperature, pressure and power sensors
of the EMRYS CREATOR showed no unexpected fluctua-
tions for the fluorination reactions.
4
. Experimental
4
.1. General experimental procedures
4.4. Fluorination of (14)
Caution: Although we have conducted these experiments
1
To a 5 mL microwave tube, charged with Selectfluor
many times at the scales reported and no uncontrolled
exothermic events or explosions have been observed, care
is advised when undertaking this procedure, due to the
(
178 mg, 0.5 mmol) was added (14) (132 mg, 0.5 mmol).
Acetonitrile (2.0 mL) was added and the tube capped. The
reaction was then irradiated to heat it to 150 8C in the
microwave cavity (at no point did the pressure inside the
tube exceed 16 atm). After 20 min, the reaction mixture was
cooled to ambient and analysed by GC–MS. The mixture
was concentrated in vacuo and the resulting solid triturated
with dichloromethane (3 ꢀ 10 mL). The combined super-
natant was concentrated in vacuo and purified via prepara-
tive HPLC (isocratic 9:1 hexane/ethyl acetate), giving a 1:1
mixture of (R) and (S)-a-cyano-4-fluoro-3-(2-fluorophe-
noxy)-benzyl (Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoroprope-
nyl)-2,2-dimethylcyclopropanecarboxylate (15) (34 mg oil,
1
potential thermal instability of Selectfluor [13,14].
1
All Sure-seal solvents and starting materials (with the
exception of (14)) are commercially available and were used
as received, without further drying or purification. EMRYS
CREATOR or EMRYS SYNTHESISER microwave reactors
from Smith Personal Chemistry were used to perform the
reactions. GC analysis was carried out using an Agilent 6890
GC with FID detector. An Restek RTX200 capillary column
was used to effect separation of the components. A typical
thermal program was 50 8C (isocratic, 2 min) 50–250 8C
(
ramp, 15 8C/min). HPLC purification was undertaken using
1
4%).
1
a Varian Prostar HPLC system, fitted with a Varian DYNA-
MAX microsorb 100-8, normal phase column under iso-
cratic conditions. NMR was carried out using either a Varian
Inova 400 or Varian Inova 500 with TMS as an internal
standard. HRMS was undertaken using a Joel GC-Mate II
mass spectrometer.
H NMR (400 MHz, CDCl ) 1.18 (3H, s, CH ), 1.29 (3H,
3
3
s, CH ), 2.00 (1H, d, J 8.0, Cl(CF )C=CHCH), 2.28 (1H, t, J
3
3
8
1
.0, CHCO C), 6.33 (1H, s, CHCN) 6.78 (1H, dd, J 9.0, J
2 F
13
.0, Cl(CF )C=CHCH), 6.90–7.30 (7H, m, Ar–H);
3
C
(
100 MHz, CDCl ) 14.6, 28.0, 29.8, 31.6, 31.8, 61.9,
3
1
3
7
1
15.5, 117.3 (d, JF 18.5), 118.7, 120.9, 123.0 (q, JF
7.5), 123.8 (d, JF 7.0), 124.9 (d, JF 4.5), 125.7 (d, JF
.0), 128.6 (d, J 5.0), 129.3, 142.7 (d, J 10.5), 145.0 (d, J
4
.2. Analysis procedures
F
F
F
19
1.5), 152.3, 152.8, 154.8, 155.4, 186.1;
F NMR
(
a) The reaction mixture was diluted with EtOAc (to 5 mL)
in a volumetric flask and 2-fluoro-biphenyl (5 mg) was
added as a standard. Identification of the products was
by GC retention time with comparison to commercial
samples. Quantification of the materials in the reaction
mixture was achieved by integration of the GC trace and
calculated against the standard added to the sample.
b) The reaction mixture was diluted with EtOAc (to 5 mL)
in a volumetric flask and 2-fluoro-biphenyl (5 mg) was
added as a standard. Identification of the products was
(
100 MHz, CDCl ) ꢁ68.76 (CF ), ꢁ128.20, ꢁ130.95
3
3
+
Ar–F); m/z (GC–MS, CI) 486 [MH] (20), 315 (10), 225
(
(
100); HRMS (EI) C H O NClF requires 485.0818 found
5
2
3
17
3
4
85.0826 (+1.8 ppm).
References
(
[
[
1] G.S. Lal, J. Org. Chem. 58 (1993) 2791–2796.
2] S. Stavber, M. Zupan, A.J. Poss, G.A. Shia, Tetrahedron Lett. 36
(1995) 6769–6772.
1
9
by F NMR using the data published by Laali and