Microwave-assisted rapid electrophilic fluorination of 1,3-dicarbonyl derivatives with Selectfluor

Article abstract of DOI:10.1016/j.jfluchem.2004.10.043

A microwave-assisted fluorination method for 1,3-dicarbonyl compounds using Selectfluor has been developed. 2-Monofluorinated products can be obtained in high yield in neutral reaction conditions with addition of 1 eq. of Selectfluor. Treatment of 1,3-dicarbonyls with 3 eq. of Selectfluor in the presence of tetrabutylammonium hydroxide (TBAH) as the base results in the formation of 2,2-difluorinated derivatives only.

Full text of DOI:10.1016/j.jfluchem.2004.10.043

Journal of Fluorine Chemistry 126 (2005) 475–478
www.elsevier.com/locate/fluor
Microwave-assisted rapid electrophilic fluorination of
1,3-dicarbonyl derivatives with Selectfluor1
*
Ji-Chang Xiao, Jean’ne M. Shreeve
Department of Chemistry, University of Idaho, ID 83844-2343, USA
Received 29 September 2004; received in revised form 20 October 2004; accepted 28 October 2004
Available online 8 December 2004
Dedicated to Professor Richard D. Chambers on the occasion of his 70th birthday.
Abstract
A microwave-assisted fluorination method for 1,3-dicarbonyl compounds using Selectfluor1 has been developed. 2-Monofluorinated
products can be obtained in high yield in neutral reaction conditions with addition of 1 eq. of Selectfluor1. Treatment of 1,3-dicarbonyls with
3 eq. of Selectfluor1 in the presence of tetrabutylammonium hydroxide (TBAH) as the base results in the formation of 2,2-difluorinated
derivatives only.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Microwave; Electrophilic fluorination; Selectfluor; 1,3-Dicarbonyl compounds
1. Introduction
acceleration for reactions carried out in a conventional
microwave oven were first observed in 1986, microwave
irradiation has found increasing application in organic
synthesis [18–20]. Recently, microwave-assisted fluorina-
tion of aromatic rings using 1 was reported [21]. Considering
the slow fluorination rates of some 1,3-dicarbonyls with 1,
we were interested in examining the impact of microwave
irradiation on yields and reaction times when mono and/or
difluorinated compounds were the desired products. As
described below, microwave methodology can play a major
role.
Electrophilic fluorination is one of the most direct and
useful methods to introduce fluorine selectively into organic
compounds [1]. There continues to be considerable interest
in the electrophilic fluorination of 1,3-dicarbonyl com-
pounds since the a-fluoro carbonyl compounds are valuable
building blocks in constructing potentially useful biological
compounds [2–14]. While 1,3-dicarbonyl derivatives can be
fluorinated directly by a variety of electrophilic fluorin-
ating agents, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo
[2.2.2]-octane bis(tetrafluoroborate) (Selectfluor1, F-TED-
A-BF4, 1), first reported by Banks et al. [15,16], is an
efficient site-selective, commercially available electrophilic
fluorinating agent. Banks et al. demonstrated the fluorination
of b-dicarbonyl compounds with 1 [17]. However, for some
substrates, long reaction times are required to bring about
those transformations.
2. Results and discussion
Under microwave irradiation conditions, 1,3-dicarbonyls
2a–d reacted readily with 1 eq. of 1 in acetonitrile to give a-
fluoro products 3a–d in 10 min (Scheme 1, Table 1).
One of the important features of these reactions is the
rapid rate. Generally, 1,3-ketoesters are less reactive than
1,3-diketones. The monofluorination of 1,3-ketoesters, 2b
and c, required 54 and 120 h, respectively, under conven-
tional reaction conditions [17]. However, while utilizing
Microwave irradiation is a powerful and easily con-
trollable heating source [18–20]. Since significant rate
* Corresponding author. Tel.: +1 208 885 6215; fax: +1 208 885 9146.
E-mail address: jshreeve@uidaho.edu (J.M. Shreeve).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.10.043

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J.-C. Xiao, J.M. Shreeve / Journal of Fluorine Chemistry 126 (2005) 475–478
Scheme 2.
Scheme 1.
microwave irradiation, we found that these reactions could
be accelerated dramatically and with comparable yields.
The microwave-assisted fluorination reactions proceeded
smoothly with essentially no tar formation despite being
carried out at approximately reflux conditions.
At the end of the reaction process, NMR spectral analyses
showed that traces of a,a-difluorinated products often
formed in these reactions. The pure products can be obtained
either via column chromatography or distillation. All of the
monofluorinated products existed predominantly in their
keto tautomers and no change was observed upon workup.
The facile monofluorination of these 1,3-dicarbonyls
prompted us to investigate the efficacy of difluorination.
Utilizing the same microwave reaction conditions, when the
highly reactive b-diketone, 2a, was treated with 3 eq. of 1,
81% yield of the corresponding a,a-difluorodiketone, 4a,
was obtained in 10 min (Scheme 2, Table 1). Under classical
reaction conditions, difluorination of 2a requires 8 days to
reach completion [17]. For the less reactive ketoesters, 2b
and c, and the ketoamide, 2d, difluorination is not complete
even when the reaction time is increased to 30 min and
the amount of 1 raised to 5 eq.. In these cases, mixtures of
mono- and difluoro-compounds were obtained (Scheme 2).
Monofluorinated 3b–d resists further fluorination under
these conditions.
Scheme 3.
difluorination reactions of 2b–d with the addition of 2 eq. of
TBAH in one pot was attempted. The desired products, 4b–
d, were obtained in high yield after microwave irradiation
for 10 min (Scheme 3, Table 1). No monofluorinated
products were observed in these reactions. To investigate the
effects of TBAH, the reaction of 2c with 3 eq. of 1 in CH3OH
(2 mL) and CH3CN (1 mL) was carried out without TBAH.
After irradiation under microwave for 10 min, the main
product was the monofluorinated compound, 3c, with a trace
of difluorinated compound, 4c. TBAH does play a key role in
the difluorination of 1,3-dicarbonyl compounds.
Fluorination of b-diesters with 1 under conventional
conditions does not occur in the absence of base [17]. This
lack of fluorination is also observed in similar reactions
with other electrophilic fluorinating reagents [10]. In our
case, microwave irradiation reactions appear to suffer from
the same limitation. However, in the presence of TBAH,
dimethyl malonate, 2e, reacted with 1 easily to give only the
difluorinated product 4e.
Our earlier work showed that tetrabutylammonium
hydroxide (TBAH) facilitated the fluorination of 1,3-
dicarbonyl compounds when electrophilic fluorination is
carried out with trifluoroamine oxide [22]. Therefore, the
Table 1
Microwave-assisted fluorination of 1,3-dicarbonyl compounds with 1
The results of the mono- and difluoro-products are
summarized in Table 1.
Substrate
Product
Yield (%)
2a
2b
2c
2d
2a
2b
2c
2d
2e
a
3a
3b
3c
3d
4a
4b
4c
4d
4e
84a
81a
70a
86a
81a
88b
78b
83b
77b
3. Conclusions
The rate of electrophilic fluorination of 1,3-dicarbonyl
derivatives with Selectfluor1 can be dramatically acceler-
ated under microwave irradiation while still retaining high
product yields. Using neutral reaction conditions, mono-
fluorination can be obtained by carefully controlling the
Isolated yields: neutral conditions.
Isolated yields: basic conditions.
b

J.-C. Xiao, J.M. Shreeve / Journal of Fluorine Chemistry 126 (2005) 475–478
477
stoichiometry of the reagents. With the addition of TBAH
as the base, difluorination can be achieved successfully in
single step reactions.
(m, 3H), 5.84 (d, J = 48.9 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H),
and 1.24 (t, J = 7.1 Hz, 3H); 19F NMR (CDCl3): d = À190.2
(d, J = 48.9 Hz, 1F).
Ethyl 2-fluoro-3-oxo-butanoate (3c) [10]: 1H NMR
(CDCl3): d = 5.16 (d, J = 49.4 Hz, 1H), 4.30 (q,
J = 7.1 Hz, 2H), 2.32 (d, J = 4.1 Hz, 3H), and 1.31 (t,
J = 7.1 Hz, 3H); 19F NMR (CDCl3): d = À193.0 (dq,
J = 49.4, 4.1 Hz, 1F).
4. Experimental
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]-
octane bis(tetrafluoroborate) (Selectfluor1, F-TEDA-BF4,
1) and all other reagents employed were purchased from
commercial sources and used without further purification.
N,N-dimethyl benzoylacetamide, 2d, was synthesized from
ethyl benzoylacetate, 2e, according to the literature [23].
CH3CN was freshly distilled under N2 from phosphorus
pentoxide prior to use. Microwave-assisted reactions were
carried out in a self-tuning single mode CEM Discoverb
Focused Synthesizer operated at 100 W. TLC analysis was
performed with Al backed plates pre-coated with silica gel
and examined under UV fluorescence (254 nm). Flash
column chromatography was executed on silica gel (Acros,
60–200 mm, 60 A). 1H and 19F NMR spectra were recorded
in CDCl3 on a 300 MHz spectrometer. Chemical shifts are
reported in ppm relative to the appropriate standards: TMS
N,N-dimethyl 2-fluoro-3-oxo-3-phenyl-propanoate (3d)
[17]: 1H NMR (CDCl3): d = 8.12 (d, J = 7.6 Hz, 2H), 7.43–
7.61 (m, 3H), 6.14 (d, J = 48.9 Hz, 1H), 3.10 (d, J = 1.8 Hz,
3H), and 2.96 (s, 3H); 19F NMR (CDCl3): d = À186.6 (d,
J = 48.9 Hz, 1F).
2,2-Difluoro-1,3-diphenylpropane-1,3-dione (4a) [24]:
1H NMR (CDCl3): d = 8.07 (d, J = 7.5 Hz, 4H), 7.45–7.66
(m, 6H); 19F NMR (CDCl3): d = À106.6 (s, 2F).
Ethyl 2,2-difluoro-3-oxo-3-phenyl-propanoate (4b) [10]:
1H NMR (CDCl3): d = 8.06 (d, J = 7.6 Hz, 2H), 7.48–7.68
(m, 3H), 4.37 (q, J = 7.1 Hz, 2H), and 1.30 (t, J = 7.1 Hz,
3H); 19F NMR (CDCl3): d = À107.6 (s, 2F).
1
Ethyl 2,2-difluoro-3-oxo-butanoate (4c) [10]: H NMR
(CDCl3): d = 4.35 (q, J = 7.1 Hz, 2H), 2.39 (t, J = 1.5 Hz,
3H), and 1.33 (t, J = 7.1 Hz, 3H); 19F NMR (CDCl3):
d = À113.7 (s, 2F).
1
as an internal standard for H NMR and CFCl3 as external
standard for 19F NMR.
N,N-dimethyl 2,2-difluoro-3-oxo-3-phenyl-propanoate
1
(4d) [17]: H NMR (CDCl3): d = 8.06 (d, J = 7.5 Hz, 2H),
4.1. General procedure for the electrophilic fluorination of
b-dicarbonyl derivatives with Selectfluor1(1) under
microwave irradiation
7.45–7.64 (m, 3H), 3.13 (t, J = 3.0 Hz, 3H), and 3.02 (s, 3H);
19F NMR (CDCl3): d = À102.7 (s, 2F).
Dimethyl 2,2-difluoro-malonate (4e) [25]: 1H NMR
(CDCl3): d = 3.92 (s, 6H); 19F NMR (CDCl3): d = À111.7
(s, 2F).
4.1.1. Neutral conditions
Into a septum-sealed microwave tube, the substrate
(1 mmol), acetonitrile (2 mL) and 1 (equivalent as required)
were charged. The resulting mixture was irradiated in a
microwave cavity at 82 8C (by modulation of power) for
10 min. The solution was cooled rapidly to room temperature
by passing compressed air through the microwave cavity. Any
insoluble material was filtered off. The solvent was removed
from the filtrate invacuo, and the crude products were purified
directly by flash chromatography over SiO2 or by distillation.
The pure products were identified by comparing their NMR
spectral data with those of literature.
Acknowledgements
The authors gratefully acknowledge the support of
AFOSR (F49620-03-1-0209), NSF (CHE0315275), and
ONR (N00014-02-1-0600).
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