Nucleophilic fluorination of β-ketoester derivatives with HBF 4

Article abstract of DOI:10.1039/c2cc37284c

Treating readily available α-diazo-β-ketoesters with HBF ₄ results in nucleophilic fluorination by the usually inert and stable tetrafluoroborate anion. The resulting α-fluoro-β-ketoesters are highly versatile synthetic intermediates, for example in the preparation of fluoro-heterocycles, as illustrated by the direct formation of fluoro-pyrimidines, -pyrazoles and -coumarins in a single step.

Full text of DOI:10.1039/c2cc37284c

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Nucleophilic fluorination of b-ketoester derivatives with HBF4w
Raffaele Pasceri, Hannah E. Bartrum, Christopher J. Hayes* and Christopher J. Moody*
Received 5th October 2012, Accepted 5th November 2012
DOI: 10.1039/c2cc37284c
Treating readily available a-diazo-b-ketoesters with HBF4 results
in nucleophilic fluorination by the usually inert and stable tetra-
fluoroborate anion. The resulting a-fluoro-b-ketoesters are highly
versatile synthetic intermediates, for example in the preparation
of fluoro-heterocycles, as illustrated by the direct formation of
fluoro-pyrimidines, -pyrazoles and -coumarins in a single step.
been exploited in O–H and N–H insertion processes leading to
useful a-alkoxy and a-amino acid derivatives.12,13 Hence the
question was whether, under appropriate conditions, fluoride
would function similarly as a nucleophile to give a-fluorocarbonyl
compounds that could be utilized in synthesis.14
Initial experiments were carried out on ethyl 2-diazo-3-oxo-
3-phenylpropanoate 1a to identify suitable conditions for the
formation of the a-fluoro-b-ketoester 2a. Although such a-fluoro-
b-ketoesters are known to be available by electrophilic fluorination
of b-ketoesters using, for example, elemental fluorine or 55%
aqueous HF/PhIO,15,16 our focus remained on nucleophilic
fluorination. A range of conditions was screened (Table 1)
starting with rhodium or copper mediated reactions of the
diazoester 1a in the presence of a variety of sources of fluoride
(Table 1, entries 1–7). Unfortunately such transition-metal
catalyzed reactions were unsuccessful with no evidence for
the formation of the desired a-fluoro-b-ketoester 2a. Instead
the reactions generally resulted in return of starting material
1a, together with general decomposition and formation of
ethyl phenylacetate formed by Wolff rearrangement, reaction
with adventitious water and subsequent decarboxylation.
Therefore we turned our attention to acid mediated processes.
Although fluorine-containing compounds are extremely rare as
natural products, an increasing number of synthetic bioactive
pharmaceuticals and agrochemicals contain fluorine.1–4 As a
consequence, a number of methods have been developed for the
introduction of fluorine into molecules by the formation of
carbon–fluorine bonds,5 most commonly involving fluorina-
tion, often of aromatic rings, using electrophilic reagents that
ultimately derive from elemental fluorine. A complementary
approach would involve the use of nucleophilic fluorination, and
indeed some very recent methods do employ fluoride.6–10 We
now report the development of methodology that is simple to
carry out, does not involve the use of exotic reagents or catalysts,
but delivers versatile a-fluoro-b-ketoester intermediates. Most
importantly it uses nucleophilic fluorination with a benign source
of fluoride, HBF4, to form the C–F bond, in a remarkable
reaction given the perceived inertness and stability of the tetra-
fluoroborate anion, representing a new alternative to existing
fluorination methodologies.
Table 1 Screening conditions for nucleophilic fluorination of ethyl
2-diazo-3-oxo-3-phenylpropanoate
Reasoning that the use of relatively unreactive sources of
nucleophilic fluoride would require the participation of a
reactive carbon electrophile, we were drawn to the possibility
of using carbene or metal carbene species. Such intermediates are
easily derived from readily available diazocarbonyl compounds,
exhibit wide ranging reactivity and versatility, and have found
extensive application in organic synthesis,11 and whilst diazo
compounds are often viewed as hazardous, a-diazo-b-ketoesters
are easier to handle than elemental fluorine, for example. Upon
treatment with transition metal catalysts (e.g. those based on
the dirhodium(II) framework), or with Bronsted or Lewis acids,
such a-diazocarbonyl compounds generate highly electrophilic
reactive intermediates that can react with a wide range of nucleo-
philes. For example, reactions with OH and NH nucleophiles have
Yield 2a
(%)
Entry F source
Conditions
a
a
b
a
1
2
3
4
KF
CsF
CsF
TBAF
Cat. Rh2(OAc)4, CH2Cl2, rt, 24 h
Cat. Rh2(OAc)4, CH2Cl2, rt, 24 h
Cat. Rh2(OAc)4, toluene, 110 1C, 24 h
Cat. Rh2(OAc)4, THF/CH2Cl2, 0 1C
to rt, 24 h
Cat. Cu(OTf)2, CH2Cl2, rt, 24 h
Cat. Cu(OTf)2, toluene, 110 1C, 24 h
Cat. Cu(OCOCF3)2, toluene, 110 1C, 24 h
Ether, 0 1C to rt, 24 h
a
b
b
c
5
6
KF
CsF
7
8
9
10
11
12
13
CsF
HFÁpyr
BF3ÁOEt2 Ether, rt, 24 h
25
45
50
82
84
BF3ÁOEt2 CH2Cl2, rt, 24 h
BF3ÁOEt2 CH2Cl2, 99 1C, 10 min, in flow
HBF4ÁOEt2 CH2Cl2, rt, 5 h
School of Chemistry, University of Nottingham, University Park,
Nottingham, NG7 2RD, UK. E-mail: chris.hayes@nottingham.ac.uk,
c.j.moody@nottingham.ac.uk
w Electronic supplementary information (ESI) available: Full experi-
mental details and copies of 1H and 13C NMR spectra for all
compounds. See DOI: 10.1039/c2cc37284c
HBF4ÁOEt2 CH2Cl2, 70 1C, 10 min, in flow
a
b
Mixture of 1a plus decomposition. Mixture of 1a plus Wolff
c
rearrangement product, PhCH2CO2Et. No reaction.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 12077–12079 12077

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Scheme 1 Proposed mechanism for nucleophilic fluorination of a-diazo-b-ketoesters with BF3; with HBF4, the reaction can be initiated by
protonation.
Since a few examples of fluorination of a-diazoketones (such as
diazoacetophenone,
PhCOCHQN2)
with
pyridinium
poly(hydrogen fluoride) (Olah’s reagent) have been reported,17
the reaction of the diazoester 1a with Olah’s reagent was
investigated (Table 1, entry 8). However, this resulted in no
reaction; presumably the diazo compound 1a, stabilized by two
carbonyl groups, is less reactive towards HF than simple diazo-
ketones. We next investigated the Lewis acid boron trifluoride
etherate since it is known to catalyze insertion reactions of
diazocarbonyl compounds.11 We were further encouraged down
this route by early work from Hooz who showed that diazo
compounds react readily with borane reagents,18 in particular the
reaction of a-diazoesters with alkyldichloroboranes that resulted
in chloride migration from boron to give a-chloroesters, in
competition with alkyl group migration.19 Thus we reasoned
that use of boron trifluoride would result in fluoride migration
to give a-fluorocarbonyl compounds.20 In the event, treatment
of the diazo compound 1a with boron trifluoride etherate in
ether or CH2Cl2 did result in the formation of the desired the
a-fluoro-b-ketoester 2a in modest yield (Table 1, entries 9 and 10).
Considering the likely mechanism of the process based on the
proposal by Hooz and Brown (Scheme 1), we reasoned that the
intermediate boron enolate requires protonation by an additional
Bronsted acid to give the final product. Hence we decided to
explore the use of HBF4 in this transformation as it combines the
components of both BF3 and HF, and were delighted to find that
the a-fluoro-b-ketoester 2a was isolated in 82% yield after 5 h
(Table 1, entry 12).
Scheme 2 Compounds: a, R = Ph (82%; 84% in flow); b, R =
2-furyl (61%; 59% in flow); c, R = 2-thienyl (76%); d, R =
PhCH2CH2 (51%); e, R = cyclohexyl (61%).
one or more heterocyclic ring, there is a huge demand for
fluorinated heterocycles. Unfortunately, with few exceptions,6–8
the methods developed for the fluorination of benzene deriva-
tives are not readily applicable to the fluorination of hetero-
aromatic rings. The methods that do exist normally rely on
electrophilic fluorination of preformed heterocyclic rings using
reagents that ultimately derive from elemental fluorine.6,7,24,25
Hence, using a-fluoro-b-ketoesters 2, obtained by nucleophilic
fluorination, as precursors might be a versatile alternative
approach to a range of fluorinated heterocycles. This is
illustrated by the preparation of fluoro-pyrimidines, -pyrazoles
and -coumarins.
For the efficient construction of a diverse range of fluorine-
containing heterocyclic rings from the a-fluoro-b-ketoesters 2,
we only considered those conversions that proceeded in a
single step leading to heterocycles with medicinal potential.
Thus reaction with resorcinols in trifluoroacetic acid26 gave
the 3-fluorocoumarins 3 in good yield (Scheme 3). Likewise
reaction with hydrazine or methylhydrazine15,27 gave the
4-fluoro-5-hydroxypyrazoles 4 in modest – good yield (Scheme 3),
with the hydroxypyrazole tautomer presumably being stabilized
over the pyrazolone form by hydrogen bonding to the adjacent
fluorine atom. Recently 4-fluoropyrazoles have attracted
some attention because of their role as biologically active
compounds,28,29 although their preparation has involved
electrophilic fluorination. As the pyrimidine heterocycle is an
important core structure in a range of biologically active
molecules,30,31 we next investigated the formation of fluorinated-
pyrimidinols from a-fluoro-b-keto esters. The reaction was simply
achieved by adding an amidine hydrochloride and DBU in
EtOH in a modification of a literature procedure,32 and gave a
range of novel 5-fluoropyrimidinols 5a–5h in moderate to
excellent yields (63–95%) (Scheme 3). Although all of the
above reactions were carried out on isolated and purified
a-fluoro-b-keto esters 2, the whole process can be telescoped
Since diazo compounds can be easily generated and handled
in flow conditions thereby reducing the hazards,13,21–23 we
showed that the fluorination reaction also proceeded readily in
a flow reactor to give a-fluoro-b-ketoester 2a in 84% yield.
These conditions also avoid the handling of possibly hazardous
a-fluorocarbonyl compounds.
These optimized conditions employing HBF4 were readily
extended to heteroaromatic b-ketoesters 1b and 1c that gave
the corresponding a-fluoro-b-ketoesters 2b and 2c in 61 and
76% yield respectively. Extension to alkyl b-ketoesters 1d and
1e gave the a-fluoro-b-ketoesters 2d and 2e in reasonable yield
(Scheme 2), with the corresponding b,b-difluoro-a-hydroxyesters,
RCF2CH(OH)CO2Et, being isolated as by products in 21 and
16% yield respectively. The byproducts are presumably formed
by carbene O–H insertion into adventitious water, followed by
conjugate addition of fluoride to the enol tautomer, dehydra-
tion and a second addition of fluoride.
b-Ketoesters are versatile intermediates in organic chemistry,
widely used in the construction of heterocycles. Given that a
large number of modern medicines and agrochemicals contain
c
12078 Chem. Commun., 2012, 48, 12077–12079
This journal is The Royal Society of Chemistry 2012

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Scheme 3 a-Fluoro-b-keto esters in the synthesis of 3-fluorocoumarins, 4-fluoropyrazoles, and 5-fluoropyrimidin-4-ols.
into a single operation obviating the need to isolate the a-fluoro-b-
keto ester. Thus the a-diazo-b-keto ester 1a was treated with
tetrafluoroboric acid etherate in dichloromethane as described
above. After 5 h, ethanol, acetamidine hydrochloride and
DBU were added sequentially to give 5-fluoro-2-methyl-6-
phenylpyrimidin-4-ol 5a in 66% yield. Likewise a-diazo-b-
keto ester 1e was converted into fluoropyrimidinol 5h in
42% yield in a single operation.
10 There are examples of fluorination by halide exchange. However this
requires the starting halo-arene or -hetarene to be (a) sufficiently
activated to SNAr reaction, and (b) readily synthetically accessible.
11 M. P. Doyle, M. A. McKervey and T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds, John Wiley,
New York, 1998.
12 D. J. Miller and C. J. Moody, Tetrahedron, 1995, 51, 10811–10843.
13 H. E. Bartrum, D. C. Blakemore, C. J. Moody and C. J. Hayes,
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In conclusion, we have developed new methodology, whereby
a-fluoro-b-ketoesters can be easily obtained by nucleophilic
fluorination with tetrafluoroboric acid, by treating readily
available a-diazo-b-ketoesters with HBF4 either using conven-
tional batch chemistry or in flow. The overall process amounts
to a novel variation on the Balz–Schiemann reaction, and the
versatility of the resulting a-fluoro-b-ketoesters is illustrated in the
synthesis of a wide range of fluoro-heterocycles. We believe that
this is an exciting development that will both complement and
challenge existing fluorination methodologies, allowing access to a
wide diversity of fluorinated pharmaceuticals and agrochemicals.
We thank the EPSRC (Grant EP/G027919/1) for support.
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c
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Chem. Commun., 2012, 48, 12077–12079 12079