Elemental fluorine. Part 9 : Catalysis of the direct fluorination of 2-substituted carbonyl compounds

Article abstract of DOI:10.1016/S0022-1139(98)00254-1

Catalysis of the reaction between fluorine and a range of 2-substituted carbonyl compounds has been investigated. Most notably, the preparation of diethyl-2-fluoromalonate has been achieved in high yield by fluorination of diethylmalonate in the presence of hydrated copper nitrate. Reactions between fluorine and carbanions derived from 2-substituted carbonyl compounds, including phosphonates, sulphones and nitriles, are also discussed.

Full text of DOI:10.1016/S0022-1139(98)00254-1

Journal of Fluorine Chemistry 92 (1998) 45±52
Elemental ¯uorine. Part 91
Catalysis of the direct ¯uorination of 2-substituted carbonyl compounds2
Richard D. Chambersa,*, John Hutchinsona,b
a Department of Chemistry, University of Durham Science Laboratories, South Road, Durham DH1 3LE, UK
b F2 Chemicals Ltd., Durham, UK
Received 4 June 1998; accepted 3 July 1998
Abstract
Catalysis of the reaction between ¯uorine and a range of 2-substituted carbonyl compounds has been investigated. Most notably, the
preparation of diethyl-2-¯uoromalonate has been achieved in high yield by ¯uorination of diethylmalonate in the presence of hydrated
copper nitrate. Reactions between ¯uorine and carbanions derived from 2-substituted carbonyl compounds, including phosphonates,
sulphones and nitriles, are also discussed. # 1998 Elsevier Science S.A. All rights reserved.
1. Introduction
slow, could be catalysed. We are now able to report that
catalysis can be achieved for the ¯uorination of many
substrates although in some cases the effect is modest
and, in others, complicating side reactions arise. In these
latter situations, alternative methods of promoting reaction
will be described.
2-Substituted-2-¯uoro carbonyl compounds are valuable
`building blocks' for the preparation of many compounds
having potentially useful biological activity and much effort
has been devoted to their preparation [2]. The ease with
which ¯uorine can be introduced into the parent 2-substi-
tuted carbonyl compounds is related to the nature and
disposition of other groups attached to the 2-carbon. Thus,
many 1,3-diketones and 1,3-ketoesters can be ¯uorinated
directly with a variety of electrophilic ¯uorinating agents
[3±12], including ¯uorine [13], and high conversions and
yields of the corresponding 2-¯uoro-compounds have been
obtained. Under comparable conditions, dialkyl malonates
are resistant to ¯uorination and in order to obtain the 2-
¯uoro-derivatives, it has been usual to treat the parent
malonates with base (most commonly, sodium hydride)
and then expose the derived carbanions to the various
¯uorinating agents [6±8,10,11,14±19], again, including
¯uorine [20].
1.1. Fluorination of dialkyl malonates
Diethyl 2-¯uoromalonate (4) is potentially a particularly
valuable `building block' and a signi®cant body of its
chemistry has already been described in the literature
[6,14,22±36]. However, the lack of a viable route to the
compound has hindered the realisation of its true potential in
synthesis.
We have now re-examined the reaction of diethyl mal-
onate (1) with ¯uorine using both formic acid and aceto-
nitrile as solvents (i.e. conditions under which ethyl
acetoacetate can be ef®ciently ¯uorinated) and have con-
®rmed that reaction is indeed very slow with only a few
percent of the substrate being converted into products after
some hours of exposure to ¯uorine. Interestingly, in neither
solvent was replacement of the 2-hydrogen the main reac-
tion. When formic acid was used as the solvent, the 19F
spectrum of the reaction product showed a doublet of
quartets at 123 ppm (JHFˆ55 and 20.9 Hz) and a triplet
of triplets at 225 ppm (JHFˆ47.4 and 28.7 Hz) in approxi-
mately equal intensities, and a much smaller doublet at
195 ppm (JHFˆ48.2 Hz) which is consistent with the
presence of the compounds CH3CHFOCOÁCH2COÁOC2H5
Copper (II) salts have been used to promote the bromina-
tion of 1,3-ketoesters [21] and this led us to investigate
whether the direct ¯uorination of dialkyl malonates, and
other compounds where direct ¯uorination is inconveniently
*Corresponding author. Tel.: +44-191-374-3120; fax: +44-191-384-
4737.
1See Ref. [1]
2Dedicated to Professor Klaus Burger on the occasion of his 60th
birthday.
0022-1139/98/$ ± see front matter # 1998 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 8 ) 0 0 2 5 4 - 1

46
R.D. Chambers, J. Hutchinson / Journal of Fluorine Chemistry 92 (1998) 45±52
Scheme 1.
Table 1
Table 2
Catalysis of the fluorination of diethyl malonate
Substrate
Catalyst
(%)
Conversion Yield(%)
(%)
Catalyst
Conversion (%)
1
2
3
Cu(NO3)2Á2.5H2O
Ni(NO3)2Á3H2O
Cr(NO3)3Á9H2Oa
Mn(NO3)Á6H2O
Fe(NO3)3Á6H2O
Co(NO3)3Á6H2O
Zn(NO3)2Á6H2O
CuCl2Á2H2O
88
70
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
CH2(COOEt)2 (1)
1
10
±
100
78 (4)
±
ca. 6
100
ca. 5%
HC(NO2)(COOEt)2 (5) 10
±
76 (8)
5
HC(Me)(COOEt)2 (6)
12
a
10
±
ca. 30
ca. 5
38
6
HC(Cl)(COOEt)2 (7)
±
10
±
78 (10)
4
ca. 5%
7
HC(F)(COOEt)2 (4)
ca. 5
ca. 5
ca. 5
±
±
±
Cu(OOCÁCH3)2ÁH2O
CuSO4Á5H2Oa
10
±
4
aOnly partially soluble.
aSee text.
(2), FCH2CH2OCOÁCH2COÁOC2H5 (3), and CH3CH2O-
COÁCHFCOÁOC2H5 (4), respectively. When the reaction
was carried out in acetonitrile, the same products were
obtained but here, attack was more site-speci®c with 2
representing some 80% of the product. The reaction in
formic acid was then carried out in the presence of a range
of salts of transition metals but no signi®cant difference in
the course of the reaction was observed. However, when the
¯uorination in acetonitrile was carried out in the presence of
a catalytic amount of hydrated copper (II) nitrate, a clean,
rapid reaction occurred and 88% of the starting material was
converted into 4 in over 80% yield (Scheme 1, Table 1,
Entry 1) ± a most remarkable catalysis.
Using diethyl malonate as a model, hydrated nitrates of
chromium, manganese, iron, cobalt, nickel and zinc were
evaluated as catalysts for the ¯uorination but, of these salts,
only nickel(II) nitrateÁ6H2O displayed catalysis (Table 1,
Entries 2 and 3). Similarly, other salts of copper were
evaluated but they did not show catalytic activity (Table 1,
Entry 4) and, furthermore, 2 was the main product as in the
case of ¯uorination in the absence of catalyst. An important
feature of the catalysed ¯uorination of diethyl malonate is
that scarcely any di¯uorination occured (vide infra). This is
very important in the context of the development of a viable
commercial process for production of diethyl ¯uoromalo-
nate, and is in contrast to the ¯uorination of the sodium salt
of diethyl malonate which gave a mixture of mono- and di-
¯uoro-compounds [20].
In the light of these ®ndings, the effect of hydrated
copper(II) nitrate on 2-substituted dialkyl malonates was
investigated (Scheme 2, Table 2).
The experiments outlined in Table 2 do not reveal the
relative reactivity of diethyl malonate 1 and diethyl nitro-
malonate 5. However, a competition experiment in which
equimolecular amounts of 1 and 5 were treated with a
de®ciency of ¯uorine in the presence of hydrated copper(II)
nitrate established that 5 is the more reactive compound.
Thus, from this experiment and results given in Table 2, it
can be deduced that reactivity is in the order EtOOCCHÁ
NO2COOEt>EtOOCCH2COOEt>EtOOCCHÁClCOOEt>
Scheme 2.

R.D. Chambers, J. Hutchinson / Journal of Fluorine Chemistry 92 (1998) 45±52
47
Scheme 3.
EtOOCCHÁFCOOEt. Signi®cant ¯uorination of diethyl
nitromalonate occurs in the absence of a catalyst and the
2-hydrogen is replaced almost exclusively (Entry 2b). This
behaviour is in sharp contrast to that of 1, 6, 7, and 4 where
replacement of hydrogen in the ethyl group (dq in 19F NMR
spectum at ca. 123 ppm) is the main process in the absence
of a catalyst.
Scheme 4.
The catalysed ¯uorination of diethyl-2-methylmalonate
(6) is not a useful method for the preparation of its 2-¯uoro-
derivative (9)* (Table 2, Entry 3a). Not only is the process
relatively slow but also, a mixture of products is obtained in
which the main components, deduced from the 19F NMR
spectrum, arise from ¯uorination at the ethyl group to give
the two diasterioisomers of CH3CHFÁOCOÁCH(CH3)-
COOCH2CH3 (11) (two doublets of quartets at 123.79
and 123.95 ppm, JHFˆ57.9 and 20.9 Hz).
other substrates discussed in this paper, using formic acid as
the solvent were unsuccessful, with the exception of ethyl
chloroacetoacetate (13). We have previously shown that, in
formic acid, the enol content of 13 is circa 15% and that
when solutions of this compound in formic acid are treated
with ¯uorine, ¯uorination is rapid until all the enol tautomer
is consumed. After this, ¯uorination is extremely slow due
to the slow enolisation of the compound in this medium
[13]. We have now found that in contrast to ¯uorinations in
acetonitrile where only copper and nickel nitrates display
catalysis, the ¯uorination of 13 in formic acid is catalysed
by salts of manganese, iron, cobalt, nickel, copper and zinc
to give the ¯uorinated product in >85% yield. Furthermore,
catalysis is not sensitive to the nature of the anion in the salt
(Scheme 4, Table 4).
1.2. Fluorination of 1,3-ketoesters
The results of our investigation into the catalysis of the
¯uorination of 1,3-ketoesters and the related N,N-diethyl
acetoacetamide (15) are outlined in Scheme 3, Table 3.
Clearly, hydrated copper(II) nitrate catalysed the ¯uorina-
tion of 12±15 to a signi®cant extent in acetonitrile but
compared to the corresponding dialkyl malonates, the pro-
cess was less ef®cient. Furthermore, 14 and to a lesser extent
13 gave more complicated mixtures of products than when
¯uorination was carried out in formic acid [13].
1.3. Fluorination of other 2-substituted carbonyl
compounds
Like the ¯uorination of dialkyl malonates, attempts to
catalyse the ¯uorination of 1,3-ketoacetates, and indeed all
Using acetonitrile as the solvent, the catalysed ¯uorina-
tion of other 2-substituted carbonyl compounds has also
been investigated (Scheme 5, Table 5). It is clear that
Table 4
Table 3
Catalyst
Conversion (%)
Substrate
Catalyst
(%)
Conversion
(%)
±
16
16
60
54
85
53
90
86
84
82
62
Cr(NO3)3Á9H2O
Mn(NO3)ÁH2O
Fe(NO3)3Á6H2O
Co(NO3)3Á6H2O
Ni(NO3)2Á3H2O
Cu(NO3)2Á2.5H2O
CuCl2Á2H2O
1a
1b
2a
2b
3a
3b
4a
4b
EtOÁOCCH2COÁCH3 (12)
2
±
2
±
2
±
2
±
45
23
40
20
90a
5
12
EtOÁOCCHClCOÁCH3 (13)
13
EtOÁOCCHCH3COÁCH3 (14)
14
Et2NÁOCCH2COÁCH3 (15)
60
46
Cu(OOCÁCH3)2ÁH2O
CuSO4Á5H2O
Zn(NO3)2Á6H2O
15
aAlthough EtOOCCFCH3COÁCH3 (18) was the main product, there were
many other minor products resulting from fluorination at other sites.

48
R.D. Chambers, J. Hutchinson / Journal of Fluorine Chemistry 92 (1998) 45±52
Scheme 5.
Table 5
Substrate
Catalyst (%)
Conversion (%)
Yield (%)
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
NCCH2COÁC(CH3)3 (20)
10
±
70
15
87
14
95
<5
46
12
54
12
52 (25) 13 (26)
±
20
CH3SO2CH2COÁCH3 (21)
10
±
45 (27) 5 (28)
±
21
(CH3O)2POÁCH2COÁCH3 (22)
10
±
20 (29) 5 (30)
±
22
NCCH2COÁOC2H5 (23)
10
±
50 (31) 8 (32)
±
52 (33) 20 (34)
23
O2NCH2COÁOC2H5 (24)
10
±
24
±
Table 6
¯uorination of all these compounds is catalysed by hydrated
copper(II) nitrate and, with the exception of phosphonate
(22) fair to good yields of mono and di¯uorinated products
were obtained. The lower yields of 29/30 can in part be
attributed to C±P bond cleavage because doublets at
ꢀFˆ 86 ppm, JFPˆ980 Hz, and at ꢀPˆ 6.9 ppm,
JFPˆ980 Hz, in the NMR spectra of the reaction mixture
indicate the formation of P±F bonds. It is probable that there
was corresponding C±S bond cleavage in the ¯uorination of
21. Yields from the ¯uorination of 20, 23, and 24 were
almost certainly reduced by some of the volatile di¯uori-
nated derivatives 26, 32 and 34 being swept from the
reaction vessel over the course of the ¯uorination process.
The ¯uorination of compounds 20±24 could also be pro-
moted by excess potassium ¯uoride (see ¯uorination of
diethyl nitromalonate [20]) (Scheme 6, Table 6) but neither
Substrate
Conversion
(%)
Yield
(%)
1
2
3
4
5
CNCH2COÁC(CH3)3 (20)
CH3SO2CH2COÁCH3 (21)
(CH3O)2POÁCH2COÁCH3 (22)
NCCH2COÁOC2H5 (23)
O2NCH2COÁOC2H5 (24)
100
90
45 (25) 6 (26)
43 (27) 4 (28)
43 (29) 7 (30)
40 (31) 25 (32)
50 (33) 7 (34)
70
62
100
of these methods gave satisfactory yields of products when
the substrates were triethyl phosphonoacetate (35), triethyl
phosphonopropionate (36), tetraisopropyl methylene diphos-
phonate (37) and ethyl methanesulphonyl acetate (38).
However, when anions of 35±38, prepared by reaction of
the parent compounds with sodium hydride were, in their
Scheme 6.

R.D. Chambers, J. Hutchinson / Journal of Fluorine Chemistry 92 (1998) 45±52
49
Scheme 7.
Table 7
Substrate
Conversion
(%)
Yield
(%)
1
2
3
4
(EtO)2POÁCH2COÁOEt (35)
(EtO)2POÁCH(CH3)COÁOEt (36)
{(i-PrO)2POÁ}2CH2 (37)
90
70
73
62
35 (39) 15 (40)
35 (41)
50 (42) 10 (43)
36 (44) 7 (45)
MeSO2CH2COÁOEt (38)
turn, treated with ¯uorine (i.e. the method that we have
already described for the ¯uorination of dialkyl malonates
[20]), fair yields of the desired ¯uoro-compounds were
obtained (Scheme 7, Table 7). Again, C±P cleavage (P±F
in NMR) reduced the yields but of course, optimisation of
the reaction conditions might be expected to give improve-
ments.
2. Mechanism
In the ¯uorination of dicarbonyl compounds such as 1,3-
diketones and 1,3-ketoesters, ¯uorine reacts with the enol
forms of the compounds and the rate of enolisation is the
rate determining step [13]. The catalytic activity of a salt
therefore must stem from the ability of the cation to accel-
erate formation of the enolate. Equally important for the
process to be catalytic is the rapid release of the metal cation
so that it can again complex with the starting material and
complete the cycle. The overall rate is, of course, dependant
on k1 and k2 (Scheme 8) which are in¯uenced by factors
such as the nature of X, Y, the anion, the cation and the
solvent. However, the interplay of these various factors is
complex and it is not surprising that a simple pattern of
catalytic activity does not emerge.
Scheme 8.
tives are required. We have previously shown that ¯uorina-
tion of carbanions derived from dialkyl malonates yields the
corresponding 2-¯uoro compounds [20], and in this paper,
we have demonstrated that this methodology can be used for
the synthesis of other 2-¯uoro-2-substituted carbonyl com-
pounds. Additionally, we have shown that the ¯uorination of
many 2-substituted carbonyl compounds, most spectacu-
larly diethyl malonate, can be catalysed by certain salts of
transition metals. Although the reactions described in this
paper have not been optimised, the results clearly demon-
strate practical methodologies which are available for the
direct ¯uorination of an ever widening range of potentially
useful `chemical building blocks'.
3. Summary
1,3-dicarbonyl compounds, such as in 1,3-diketones and
1,3-ketoesters can react with ¯uorine to yield the corre-
sponding 2-¯uoro- compounds directly [13,37]. However,
when the combined effects of a carbonyl group and other
groups attached to the 2-carbon atom are less activating,
other approaches to preparing the required 2-¯uoro-deriva-
4. Experimental
Except where indicated otherwise, 1H;19 F and 31P NMR
spectra were recorded on a Bruker AC250 spectrometer
operating at 250 MHz for hydrogen, 235 MHz for ¯uorine
or 101 MHz for phosphorus. 13C NMR spectra were mea-

50
R.D. Chambers, J. Hutchinson / Journal of Fluorine Chemistry 92 (1998) 45±52
1
sured on a Varian VXR 400 spectrometer operating at
100 MHz or a Varian Gemini 200 spectrometer operating
at 50 MHz. Chemical shifts (CDCl3) are recorded in ppm
from tetramethyl silane, ¯uorotrichloromethane and phos-
phoric acid, and coupling constants are in Hz. Mass spectra
were measured on a Fisons Trio 1000 mass spectrometer
coupled to a Hewlett Packard 5890 II gas chromatograph
®tted with a silicone elastomer coated column (SE 30; 25 m;
0.2 mm i.d.). Accurate mass measurements were deter-
mined at the EPSRC Mass Spectrometry Service Centre,
Swansea, UK. Pure samples were isolated by GC (4 m
SE30) unless indicated otherwise.
(s, CH3), 62.7 (s, CH2), 85.3 (d, JCFˆ196.6, CHF), 163.9
‡
‡
2
(d, JCFˆ24.1, CO); m/z (CI , NH3) 196 ((M‡NH4) ,
100%).
Fluorination of diethyl 2-nitromalonate (5). Diethyl-2-
¯uoro-2-nitromalonate, C2H5OÁOCCF(NO2)COÁOC2H5 (8)
[8], ꢀHˆ1.40 (3H, t, JHHˆ7.1, CH3), 4.47 (2H, q, JHHˆ7.12,
CH2); ꢀFˆ 127.3 (s); ꢀCˆ13.7 (s, CH3), 65.2 (s, CH2),
106.3 (d, 1JCFˆ261.7, CNO2F), 157.9 (d, 2JCFˆ25.2, CO).
Fluorination of diethyl 2-chloromalonate (7). Diethyl 2-
chloro-2-¯uoromalonate, C2H5OÁOCCFClCOÁOC2H5 (9)
[7], ꢀHˆ1.35 (3H, t, JHFˆ7.0, CH3), 4.39 (2H, q, JHFˆ7.0,
‡
‡
CH2); ꢀFˆ 121.0 (s); m/z (CI , NH3) 230 ((M‡NH4) ,
In these experiments two basic procedures, `a' and `b',
were used.
100%) for 35Cl.
Fluorination of ethyl acetoacetate (12). Ethyl 2-¯uoro-
acetoacetate, CH3COCHFCOOC2H5 (16) [10,39], ꢀHˆ1.34
(3H, t, JHHˆ7.2, CH3CH2) 2.35 (3H, d, JHHˆ4.0, COCH3)
4.32 (2H, q, JHHˆ7.1, OCH2) 5.2 (1H, d, JHFˆ49.3, CHF);
4.1. Procedure `a'
‡
A glass reaction vessel ®tted with a PTFE coated mechan-
ical stirrer, a FEP thermocouple well, a FEP gas delivery
tube and an exit tube to a scrubber ®lled with soda lime was
charged with diethyl malonate (3.2 gm, 20 mmol), cupric
nitrate 2.5H2O (0.46 gm, 2.0 mmol) and acetonitrile (50 ml)
before being cooled to 5±88C. The vessel was purged with
nitrogen and then ¯uorine diluted to 10% v/v with nitrogen
was passed through the stirred solution at a rate of
ꢀFˆ 193.7 (d, JHFˆ49.4); m/z 148 (M ) 106 (M-CH2CO)
43 (CH3CO).
Fluorination of ethyl 2-chloroacetoacetate (13). Ethyl 2-
chloro-2-¯uoroacetoacetate, CH3COCClFCOOC2H5 (17)
[8], ꢀHˆ1.36 (3H, t, JHHˆ7.1, CH3CH2), 2.46 (3H, d,
JHFˆ2.6, CH3CO), 4.39 (2H, q, JHHˆ7.3, CH3CH2);
ꢀFˆ 123.5 (m); m/z 183 (M‡1) 43 (CH3CO) for 35Cl.
Fluorination of ethyl 2-methylacetoacetate (14). Ethyl
2-¯uoro-2-methylacetoacetate, CH3COCF(CH3)COOC2H5
(18) [10], ꢀHˆ1.31 (3H, t, JHHˆ7.1, CH3CH2), 1.69 (3H, d,
JHFˆ22.2, CH3CF), 2.33 (3H, d, JHFˆ4.6, COCH3), 4.28
1
16 mmol h for 4 h. When the ¯uorine supply had been
turned off, the reaction vessel was purged with nitrogen. The
reaction mixture was then poured into water and extracted
with dichloromethane. A weighed amount of tri¯uoro-
methylbenzene was added to the extracts whose 19F
NMR spectrum was then measured. The dried extracts were
evaporated and the residue was analysed by GLC and or 1H
NMR. From this information, the amount of substrate
converted (conversion) and yield of product, based on the
amount of substrate converted, were calculated. A sample of
pure product was obtained by preparative scale GC and
identi®ed as diethyl-2-¯uoromalonate.
(2H, q, JHHˆ7.1, CH2); ꢀFˆ 157.7 (qq, JHFˆ22.1, JHF
ˆ
‡
4.5); m/z 163 (M ‡1) 120 (M-CH2CO) 43 (COCH3).
Fluorination of N,N-diethyl acetoacetamide (15). Puri®-
cation by column chromatography (SiO2/ethyl acetate)
gave N,N,-diethyl-2-¯uoroacetoacetamide, CH3COCHF-
COÁN(C2H5)2 (19) (nc), (Found: C, 54.3; H, 8.1; N, 7.8.
C8H14NO2 requires C, 54.8; H, 8.0; N, 8.0%); ꢀHˆ1.00 (3H,
t, JHHˆ7.0, CH2CH3), 1.08 (3H, t, JHHˆ7.2, CH2CH3), 2.18
(3H, d, Jˆ4.0, CH3COCHF), 3.26 (4H, m, N(CH2CH3)2),
5.3 (1H, d, JHFˆ49.9, CHF); ꢀFˆ 188.7 (dd, JHFˆ49.5,
JHFˆ4.3); ꢀC 12.20 (s, CH2CH3), 13.90 (s, CH2CH3), 25.73
(s, CH3CO), 40.41 (s, CH2CH3), 41.47 (s, CH2CH3), 91.25
4.2. Procedure `b'
1
A similar vessel to that described in `a' was purged with
nitrogen and charged with degreased sodium hydride
(0.72 gm, 30 mmol). Dry acetonitrile (35 ml) was added
to the hydride followed by the dropwise addition, with
stirring, of triethyl-2-phosphonopropionate (4.47 gm,
20 mmol) in dry acetonitrile (15 ml). After addition of
the substrate, the mixture was stirred for ca. 1 h before
10% ¯uorine in nitrogen was passed through it for 4 h as
described above. When ¯uorination was ®nished and the
reaction vessel purged, water was slowly added to hydrolyse
excess hydride. Extraction and the remaining work up was
as described in `a'.
(d, JCFˆ194.9, CHF), 162.8 (d, 2JCF 20.2, CO.N<), 201.7
‡
2
(d, JCFˆ24.0, CH3COCHF); m/z 175(M ).
Fluorination of 4,4-dimethyl-3-oxo-pentane nitrile (20).
4,4-dimethyl-3-oxo-2-¯uoropentane nitrile, CNCHFCOÁ
C(CH3)3 (25) (nc), (HRMS (NH3/CI), Found: 161.1090;
‡
C7H14FN2O (M‡NH4) requires 161.1090); ꢀHˆ1.31 (9H,
s), 5.69 (1H, d, JHFˆ47.0); ꢀFˆ 192.3 (d, JHFˆ47.0); ꢀCˆ
4
3
25.76 (d, JCFˆ2.3, CH3), 44.29 (d, JCFˆ2.7, (CH3)3C),
1
2
79.08 (d, JCFˆ199.2, CFH), 112.29 (d, JCFˆ29.7, CN),
‡
‡
200.59 (d, 2JCFˆ17.9, CO); m/z (CI , NH3) 161 (M‡NH4)
11%, 101 (100). 4,4-dimethyl-3-oxo-2,2-di¯uoropentane
nitrile, CNCF2CO.C(CH3)3 (26) (not pure), ꢀHˆ1.34 (s);
ꢀFˆ 94.2 (s); ꢀCˆ30.02 (s, CH3), 47.68 (s, (CH3)3C),
Fluorination of diethyl malonate (1). Diethyl-2-¯uoro-
malonate, C2H5OÁOCCHFCOÁOC2H5 (4) [38], ꢀHˆ1.41
(3H, t, Jˆ7.1, CH3), 4.4 (2H, q, Jˆ7.2, CH2), 5.36 (1H,
d, JHFˆ48.3, CHF); ꢀFˆ 196.5 (d, JHFˆ48.3); ꢀCˆ13.9
1
2
109.63 (t, JCFˆ262.47 CF2), 114.25 (t, JCFˆ42.14,
‡
2
CN), 200.40 (t, JCFˆ25.34, CO); m/z (CI , CH4) 162
‡
(M‡1) 22%, 85 (100).

R.D. Chambers, J. Hutchinson / Journal of Fluorine Chemistry 92 (1998) 45±52
51
Fluorination of 1-methanesulphonylpropan-2-one (21).
1-Fluoro-1-methanesulphonylpropan-2-one, CH3SO2CHF-
COÁCH3 (27) (nc), (Found: C, 31.0; H, 4.4. C4H7FO3S
JHFˆ46.8, JHPˆ11.7); ꢀFˆ 211 (dd, 2JFPˆ71.9,
JHFˆ46.8); ꢀPˆ10.3 (d, JFPˆ71.9); ꢀCˆ(100 MHz) 13.5
3
(s, COOCH2CH3), 15.8 (d, JCPˆ5.7, OCH2CH3), 61.8
‡
2
4
requires C, 31.2; H, 4.5%, HRMS, Found; (M‡NH4)
(s, COOCH2CH3), 63.7 (t, JCP ˆ JCFˆ6.3, OCH2CH3),
84.4 (dd, 1JCFˆ195, 1JCPˆ158, CHF), 164.3 (d, 2JCFˆ21.7,
172.0444 C4H11FNO3S requires 172.04437); ꢀHˆ2.5 (3H,
d, 4JHFˆ3.6, COÁCH3), 3.1 (3H, d, 4JHFˆ2.2, SOÁCH3), 5.6
‡
‡
CO); m/z (CI , NH3) 260 ((M‡NH4) 100%). Triethyl 1,1-
di¯uorophosphonoacetate, (C2H5O)2POÁCF2COÁC2H5 (40)
2
2
(1H, d, JHFˆ48.0, CHF); ꢀFˆ 183.7 (dm, JHFˆ47.0);
‡
1
ꢀCˆ27.8 (s, CH3S), 38.1 (s, CH3C), 100.4 (d, JCFˆ231,
(nc), (HRMS, Found: (M‡NH4) 278.0969. C8H19F2NO5P
‡
2
CHF), 196.0 (d, JCFˆ20.4, CO); m/z (CI , NH3) 172
requires 278.0969); ꢀHˆ1.4 (3H, m), 4.4 (2H, m); ꢀPˆ2.96
‡
2
((M‡NH4) , 100%). 1,1-Di¯uoro-1-methanesulphonylpro-
(t, JFPˆ96.2); ꢀFˆ 117 (d, JFPˆ96.2); ꢀCˆ(100 MHz)
3
pan-2-one, MeSO2CF2COÁMe (28) (not pure), ꢀFˆ 113.3
13.4 (s, COOCH2CH3), 15.9 (d, JCPˆ5.3, OCH2CH3),
‡
‡
2
(s); m/z (CI , NH3) 190 ((M‡NH4) , 100%).
63.4 (s, COOCH2CH3), 65.2 (d, JCPˆ6.5, OCH2CH3),
1
1
Fluorination of dimethyl-2-oxypropyl phosphonate (22).
Dimethyl-1-¯uoro-2-oxypropyl phosphonate, (CH3O)2-
110.7 (dt, JCFˆ271, JCPˆ203, CF2), 161.4 (q,
‡ ‡
2JCFˆ18.3, CO); m/z (CI , NH3) 278 ((M‡NH4) 100%).
Fluorination of triethyl 2-phosphonopropionate (36).
(SiO2/Ethyl acetate) Triethyl 2-¯uoro-2-phosphonopropio-
nate, (C2H5O)2POÁC(CH3)FCOÁOC2H5 (41) (nc), (HRMS,
‡
POÁCHFCOÁCH3 (29) (nc), (HRMS, Found: (M‡NH4)
202.0644. C5H14FNO4P requires 202.0644); ꢀHˆ2.39
4
2
(3H, d, JHFˆ4.5, COÁCH3), 3.9 (6H, d, d, JHPˆ10.8,
‡
2
2
Jˆ2.9, CH3OP), 5.25 (1H, d,d, JHFˆ47.7, JHPˆ14.4,
Found: (M‡NH4) 274.1220; C9H22FNO5P requires
2
2
4
CHF); ꢀFˆ 208 (ddq, JFPˆ71.3, JHFˆ47.8, JHFˆ4.5);
274.1220); ꢀHˆ1.3 (9H, m), 1.8 (3H, dd, JHFˆ23.4,
2
2
ꢀPˆ12.7 (d, JFPˆ71.2); ꢀCˆ(50 MHz) 26.5 (s, CH3OÁC),
JHPˆ15.1), 4.2 (6H, m); ꢀFˆ 172 (dq, JFPˆ83.3,
2
4
2
54.2 (dd, JCPˆ6.6, JCFˆ2.0, CH3OP), 91.0 (dd,
3JHFˆ23.4); ꢀPˆ13.4 (d, JFPˆ83.3); ꢀCˆ(100 MHz) 13.7
1JCFˆ196.5, JCPˆ152.5 CHF), 200.5 (d, JCFˆ20.2,
(s, COOCH2CH3), 16.1 (s, OCH2CH3), 19.9 (d, 2JCFˆ21.8
1
2
‡
‡
2
CFHCO); m/z (CI , NH3) 202 ((M‡NH4) , 10%).
CH3CF), 62.1 (s, COOCH2CH3), 64.0 (dd, JCPˆ19.1,
1
1
Dimethyl-1,1-di¯uoro-2-oxypropyl phosphonate, (CH3O)2-
2
4JCFˆ6.5 OCH2CH3), 92.7 (dd, JCF, JCPˆ165 and 193,
‡
POÁCF2COÁCH3 (30) (not pure), ꢀFˆ 117.7 (d, JFPˆ97);
CF), 167.6 (dd, 2JCFˆ22.5, 2JCPˆ4.9 CO); m/z (CI , NH3)
‡
‡
‡
2
ꢀPˆ5.9 (d, JFPˆ97); m/z (CI , NH3) 220 ((M‡NH4) ,
274 ((M‡NH4) , 100%).
100%).
Fluorination of ethyl cyanoacetate (23). Ethyl cyano¯uor-
oacetate, NCCHFCOÁOC2H5 (31) [40], (HRMS (NH3/CI),
Fluorination of tetraisopropyl methylenediphosphonate
(37). (SiO2/Ethyl acetate) Tetraisopropyl ¯uoromethylene-
diphosphonate, {((CH3)2CH)2POÁ}2CHF (42) (nc), (HRMS,
‡
‡
Found: 149.0730; C5H10FN2O2 (M‡NH4)
requires
Found: (M‡NH4) 380.1767; C13H33FNO6P2 requires
149.0726); ꢀHˆ1.39 (3H, t, JHHˆ7.14, CH3), 4.42 (2H, q,
JHHˆ7.14, CH2), 5.50 (1H, d, JHFˆ46.3, CHF); ꢀFˆ 194.6
(d, JHFˆ46.3); ꢀCˆ13.89 (s, CH3), 64.31 (s, (CH2), 74.28 (d,
380.1767); ꢀHˆ1.37 (12H, d, JHHˆ6.2), 1.38 (12H, d,
2
JHHˆ6.2), 4.8 (5H, m); ꢀFˆ 227 (dt, JHFˆ46, JFPˆ64);
2
ꢀPˆ9.7 (d, JFPˆ64); ꢀCˆ(100 MHz) 23.6 (m, CH3), 24.1
1JCFˆ196.8, CFH), 111.62 (d, JCFˆ29.8, CN), 160.64 (d,
(d, JCPˆ11.9, CH3), 72.7 (d, JCFˆ37.8, CH(CH3)), 84.3
2
3
2
‡
‡
‡
2JCFˆ24.7, CO); m/z (CI , NH3) 149 (M‡NH4) 3%, 61
(dt, JCFˆ191.5, JCP 158, CFH); m/z (CI , NH3) 380
1
1
‡
(100). Ethyl cyanodi¯uoroacetate, NCCF2COÁOC2H5 (32)
((M‡NH4) , 24%). Tetraisopropyl di¯uoromethylenedi-
‡
‡
(not pure), ꢀFˆ 97.4 s); m/z (CI , CH4) 150(M‡1) 46%,
phosphonate, {((CH3)2CH)2POÁ}2CF2 (43) (nc), (HRMS,
‡
122 (100).
Fluorination of ethyl nitroacetate (24). Ethyl ¯uoroni-
troacetate, O2NCHFCOÁOC2H5 (33) [41], (HRMS
Found: (M‡NH4) 398.1673; C13H32F2NO6P2 requires
398.1673); ꢀHˆ1.44 (3H, d, JHHˆ6.2), 1.46 (3H, d,
2
JHHˆ6.2), 4.97 (1H, m); ꢀPˆ2.3 (t, JFPˆ87); ꢀFˆ 123
‡
2
(CH4/CI), Found: 152.0312; C4H7FNO4 (M‡1) requires
(t, JFPˆ87); ꢀCˆ(100 MHz) 23.5 (s, CH3), 24.1 (s, CH3),
1
1
152.0391); ꢀHˆ1.38 (3H, t, JHHˆ7.1, CH3), 4.42 (2H, q,
JHHˆ7.1, CH2), 6.06 (1H, d, JHFˆ46.4, CHF); ꢀFˆ 150.5
(d, JHFˆ48.4); ꢀCˆ13.75 (s, CH3), 64.58 (s, CH2), 102.72
74.6 (s, CH(CH3)), 115.5 (tt, JCFˆ278.8, JCPˆ189.6,
‡ ‡
CF2); m/z (CI , NH3) 398 ((M‡NH4) , 39%).
Fluorination of ethyl methanesulphonylacetate (38).
(SiO2/DCM) Ethyl methanesulphonyl ¯uoroacetate,
CH3SO2CHFCOÁOC2H5 (44) (nc), (Found: C, 32.3; H,
4.7; C5H9FO4S requires C, 32.6; H, 4.9%); ꢀHˆ1.42 (3H,
t, JHHˆ6.0), 3.1 (3H, d, JHFˆ2.2), 4.42 (2H, q, JHHˆ7.0),
5.6 (1H, d, JHFˆ47.4); ꢀFˆ 184 (dq, JHFˆ47.3, 4JHFˆ2.2);
ꢀCˆ(50 MHz) 13.7 (s, CH2CH3), 37.4 (s, SCH3), 63.6 (s,
‡
(d, 1JCFˆ248.9, CFH), 159.0 (d, 2JCFˆ24.8, CO); m/z (CI ,
‡
CH4) 152(M‡1) 21%, 124 (100). Ethyl di¯uoronitroace-
tate, O2NCF2COÁOC2H5 (34) [41,42], ꢀHˆ1.41 (3H, t,
JHHˆ7.1, CH3), 4.49 (2H, q, JHHˆ7.1, CH2); ꢀFˆ 92.8
(s); ꢀCˆ13.6 (s, CH3), 65.8 (s, (CH2), 112.9 (t, 1JCFˆ297.5,
‡
‡
CF2), 155.9 (t, 2JCFˆ31.3, CO); m/z (CI , CH4) 170(M‡1)
1
2
16%, 74 (100).
Fluorination of triethyl phosphonoacetate (35). (SiO2/
Ethyl acetate) Triethyl 1-¯uorophosphonoacetate,
CH2), 96.5 (d, JCF CHF), 161.2 (d, CO, JCFˆ23.1); m/z
‡ ‡
(CI , NH3) 202 ((M‡NH4) , 35%). Ethyl methanesulpho-
nyl di¯uoroacetate, CH3SO2CF2CO.OC2H5 (45), (not pure)
ꢀFˆ 111 (s); ꢀHˆ1.38 (3H, t, JHHˆ7.1), 3.13 (3H, s), 4.55
(C2H5O)2POÁCHFCOÁOC2H5 (39) [12,43,44], (HRMS,
‡
‡
‡
Found: (M‡NH4) 260.1063; C8H20FNO5P requires
(2H, q, JHHˆ7.1); m/z (CI , NH3) 220 ((M‡NH4) , 3%),
203 (M‡1, 2), 63 (100).
260.1063); ꢀHˆ1.3 (9H, m), 4.3 (6H, m), 5.2 (1H, dd,

52
R.D. Chambers, J. Hutchinson / Journal of Fluorine Chemistry 92 (1998) 45±52
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