Synthesis of α-fluorinated phosphonoacetate derivatives using electrophilic fluorine reagents: Perchloryl fluoride versus 1-chloromethyl-4- fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor)

Article abstract of DOI:10.1016/j.jfluchem.2005.04.002

Triethyl fluorophosphonoacetate and triethyl difluorophosphonoacetate are directly synthesized from triethyl phosphonoacetate by treatment with NaH and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor). Contrary to a recent report [C.J. Hamilton, S.M. Roberts, J. Chem. Soc., Perkin Trans. 1 (1999) 1051-1056], the reaction proceeded in THF without the need for DMF as a co-solvent. This method is more selective and provides greater convenience and safety than fluorination of the same substrate by treatment with t-BuOK and perchloryl fluoride (FClO₃) in toluene while offering advantages over a number of previously described methods employing alternative electrophilic fluorinating reagents or other approaches. Either the monofluoro or the difluoro product can be obtained predominantly by adjusting the molar ratio of base and Selectfluor. Triethyl 2-fluoro-2-phosphonopropionate (ethyl 2-(diethoxyphosphinyl)-2-fluoropropanoate) is also more conveniently made from triethyl 2-phosphonopropanoate using NaH/Selectfluor in THF than with FClO₃/t-BuOK in toluene. Detailed procedures are given for obtaining the corresponding triacids in quantitative yield from the fluorinated triesters by P,P-silyldealkylation with bromotrimethylsilane followed by one-pot double hydrolysis with H₂O, and isolation as stable dicyclohexylammonium (DCHA) or pyridinium (Py) salts. Substitution of EtOH for H₂O in the latter procedure provides the CO-ester phosphonic diacids, isolated as DCHA salts, in one step. ¹H, ¹³C, ³¹P and ¹⁹F NMR data are given for the compounds prepared.

Full text of DOI:10.1016/j.jfluchem.2005.04.002

Journal of Fluorine Chemistry 126 (2005) 1467–1475
www.elsevier.com/locate/fluor
Synthesis of a-fluorinated phosphonoacetate derivatives using
electrophilic fluorine reagents: Perchloryl fluoride versus
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (Selectfluor1)
Mong S. Marma, Leslie A. Khawli 1, Vahak Harutunian,
*
Boris A. Kashemirov, Charles E. McKenna
Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744, USA
Received 14 December 2004; received in revised form 13 April 2005; accepted 15 April 2005
Abstract
Triethyl fluorophosphonoacetate and triethyl difluorophosphonoacetate are directly synthesized from triethyl phosphonoacetate by
treatment with NaH and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor1). Contrary to a recent
report [C.J. Hamilton, S.M. Roberts, J. Chem. Soc., Perkin Trans. 1 (1999) 1051–1056], the reaction proceeded in THF without the need for
DMF as a co-solvent. This method is more selective and provides greater convenience and safety than fluorination of the same substrate by
treatment with t-BuOK and perchloryl fluoride (FClO3) in toluene while offering advantages over a number of previously described methods
employing alternative electrophilic fluorinating reagents or other approaches. Either the monofluoro or the difluoro product can be obtained
predominantly by adjusting the molar ratio of base and Selectfluor1. Triethyl 2-fluoro-2-phosphonopropionate (ethyl 2-(diethoxypho-
sphinyl)-2-fluoropropanoate) is also more conveniently made from triethyl 2-phosphonopropanoate using NaH/Selectfluor1 in THF than with
FClO3/t-BuOK in toluene. Detailed procedures are given for obtaining the corresponding triacids in quantitative yield from the fluorinated
triesters by P,P-silyldealkylation with bromotrimethylsilane followed by one-pot double hydrolysis with H2O, and isolation as stable
dicyclohexylammonium (DCHA) or pyridinium (Py) salts. Substitution of EtOH for H2O in the latter procedure provides the CO-ester
1
phosphonic diacids, isolated as DCHA salts, in one step. H, 13C, 31P and 19F NMR data are given for the compounds prepared.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Triethyl fluorophosphonoacetate; Triethyl difluorophosphonoacetate; Electrophilic fluorination; Selectfluor1; Perchloryl fluoride; Triethyl
fluorophosphonopropionate; Fluorophosphonoacetic acid; Difluorophosphonoacetic acid
1. Introduction
carbocyclic nucleoside monophosphates form inhibitors of
HIV reverse transcriptase [5].
a-Fluorinated derivatives of trialkyl phosphonoacetates
(1) are useful precursors to the corresponding monofluoro-
(2e) or difluoro- (3e) phosphonoacetic acids [1–3], which
inhibit DNA polymerases [4], and in conjugation with
When fluorine is substituted for one or both a-hydrogens
in phosphonoacetic acid (1e), the resulting steric perturba-
tion is relatively small, but the acid–base properties of the
fluorinated derivatives are modified significantly [2],
analogously to a-fluorinated methylenebisphosphonates
[6–8]. Fluorine substitution also introduces a potentially
useful 19F NMR probe [9] into these molecules and, in
monofluoro-substituted phosphonoacetates, creates a chiral
center that has possible value in probing stereochemical
interactions. In addition, triethyl fluorophosphonoacetate
* Corresponding author. Tel.: +1 213 740 7007; fax: +1 213 740 0930.
E-mail address: mckenna@usc.edu (C.E. McKenna).
1
Current address: Department of Pathology, Keck School of Medicine,
University of Southern California, Los Angeles, CA 90089, USA.
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.04.002

1468
M.S. Marma et al. / Journal of Fluorine Chemistry 126 (2005) 1467–1475
(2a) is a convenient starting point for preparation of cognate
compounds, such as triethyl chlorofluoro- and bromofluor-
ophosphonoacetate [10] and their corresponding acids [11],
and has been used as a Wittig-Horner reaction partner for the
synthesis of a-fluoro-a,b-unsaturated esters [12] and a
fluorinated PGE1 analogue [13].
observed (by TLC) in THF alone, and the added DMF was
found to impair product recovery. Difluorination was not
reported by these authors. The final triacid was prepared in
several steps by sequential treatment of 2a with NaOH (to
de-esterify the –CO2Et), BTMS and H2O [5].
We report here that treatment in THF with NaH followed
by Selectfluor1 can be used in place of t-BuOK/FClO3 for
direct fluorination of triethyl phosphonoacetate 1a to
produce predominantly either mono (2a) (40%, isolated)
or difluorinated product (3a) (69%, isolated) by adjusting the
molar ratio of NaH and Selectfluor1. Besides being a more
practical, convenient and safer alternative to FClO3, the new
NaH/Selectfluor1-THF method is more selective, allowing
preparation of 2a or 3a in single step. Similarly, 5a was
prepared in THF in excellent yield (85%, isolated) from
triethyl phosphonopropionate 4a. The corresponding tria-
cids were obtained in one pot by conversion to the ethyl P,P-
bis(TMS) esters with BTMS [25,26] and addition of water:
the resulting phosphonic diacids lower the pH sufficiently to
promote subsequent acid hydrolysis of the remaining
carboxylate ester group on warming. Alternatively, the
isolable, mixed alkyl silyl intermediate esters can be
transformed into the CO–ethyl phosphonic diacids (e.g.
2c, 3c) by reaction with wet EtOH.
The monofluoro ester 2a has been obtained previously by
the reaction of ethyl bromofluoroacetate with triethyl
phosphate [14], or of ethyl chlorofluoroacetate with sodium
diethyl phosphate [15], and more recently, from metalation
of (EtO)2P(O)CFHBr with Zn, followed by reaction of the
resulting organozinc compound with ethyl chloroformate
[16]. A similar route to 3a via generation of an organozinc
reagent from (EtO)2P(O)CF2Br followed by CuBr-catalyzed
reaction with ethyl chloroformate has been described [17].
P,P-diethyl difluorophosphonoacetic acid (3d) was prepared
by CO2-carboxylation of lithium diethyl difluoromethylpho-
sphonate [5].
Some years ago, the senior author and independently
Blackburn reported the synthesis of a-fluorinated tetraalkyl
methylenebisphosphonates (formerly, methanediphospho-
nates) via fluorination of tetraalkyl methylenebisphospho-
nate carbanions with perchloryl fluoride [6,7]. a-Fluorinated
methylenebisphosphonic acids are interesting analogues of
pyrophosphoric acid and as such have led to the synthesis of
related fluoromethylenebisphosphonate nucleotide analo-
gues [18–24].
2. Results and discussion
Our laboratory briefly communicated extension of this
method to prepare 2a, 3a, and 5a providing the correspond-
ing acids and C-ethyl diacids [1]. However, subsequent
commercial unavailability of FClO3 and the hazards
attending synthesis of this reagent have impeded use of
this approach, and alternative methods have been sought
(Fig. 1).
Perchloryl fluoride reacts smoothly at 10–20 8C with
triethyl phosphonoacetate 1a potassium anion in toluene to
give the monofluoro and difluoro esters 2a and 3a. The
fluorination reaction proceeds as a titration of the anion with
perchloryl fluoride and can be followed visually as the
poorly soluble potassium salt of 1a disappears. Completion
of the reaction is easily detected by monitoring FClO3
uptake using gas bubblers and is also signaled by a color
change from yellow-orange to pale yellow. Appropriate
safety procedures must be followed, notably, use of
fluorocarbon grease and avoidance of contact between
FClO3 and combustible substances [6]. Results illustrating
the influence of base source and ratio on product yields are
summarized in Table 1. At varying ratios of t-BuOK
(preferred over Na) to 1a (1.0–1.7 eq.), mixtures of 2a:3a
Recently, Hamilton [5] evaluated N-fluoro-o-benzenedi-
sulfonamide
(NFOBS),
N-fluorobenzenesulfonamide
(NFSI) and 1-chloromethyl-4-fluoro-1,4-diazoniabicy-
clo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor1) as
possible ‘‘electrophilic fluorine’’ agents for preparation of
2a directly from 1a. Of these, Selectfluor1 was found to
fluorinate the sodio carbanion of triethyl phosphonoacetate
in THF-DMF, but yields were low (17%). No product was
Table 1
Fluorination of 1a with FClO3a. Effect of base on product distribution
Base: 1a
% Yieldb
Base
Ratio
2a
3a
Na
1:1
28
43
39
35c
20 (12)d
28 (4)d
35 (10)d
45c (16)d
t-BuOK
t-BuOK
t-BuOK
1:1
1.3:1
1.7:1
a
Reaction conditions: vd. Experimental.
31P NMR yield.
b
c
d
Isolated yield.
Fig. 1. Structures of phosphonoacetates and a-fluorinated derivatives.
Side product derived from P–C cleavage of 3a.

M.S. Marma et al. / Journal of Fluorine Chemistry 126 (2005) 1467–1475
1469
nucleophilic fluorination, as illustrated in conversion of
a-hydroxybenzyl phosphonate esters into a-fluoro esters by
diethylamino sulfur trifluoride (DAST) [35] depends upon
availability of the a-hydroxy phosphonoacetate. Fluorina-
tion of trialkyl bromo- or chlorophosphonoacetate with
CaF2-supported KF [36,37] is a further possibility, provided
the monohalosubstrate proves sufficiently reactive. How-
ever, since the initial finding that perfluoro-N-fluoropiper-
idine can convert the sodium salt of 2-nitropropane and
diethyl malonate to 2-fluoro-2-nitropropane and diethyl
difluoromalonate, respectively, there has been an increasing
focus on N–F fluorinating agents [38–40]. Among them,
notable are N-fluoropyridine-2 (1H)-one [41], N-fluoro-N-
alkylsulfonamides [42], N-fluoropyridinium salts [43], and
finally 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]
octane bis(tetrafluoroborate) (Selectfluor1) [44–46].
Scheme 1. Preparation of mono- and difluorophosphonoacetates.
were formed varying in composition from 4:3 to 7:8. If both
2a and 3a are desired, the synthesis then provides both
together in ꢀ80% total yield and approximately in equal
proportion. Reaction at higher temperatures gave decreased
yields due to excessive product breakdown (data not shown).
Increased conversion to 3a at higher base:1a ratios was
limited by more extensive formation of a side product with
dP = 0.2 ppm (s) (Table 1, 6). This compound presumably
arises from base-mediated cleavage of a C–P bond in 3a as
no 19F-splitting of the 31P NMR signal is observed. Cleavage
of a CF2–P bond, assumed to follow attack of base at
phosphorus, occurs in tetraethyl difluoromethylenebispho-
sphonate under similar reaction conditions but in 3a, where
the ester carbonyl presents an alternative target to a basic
nucleophile base, CF2–P(O) bond breaking is evidently
preferred over CF2–C(O) bond breaking.
It was previously reported [5] that treatment of the
sodium salt of 1a in THF with Selectfluor1 gave no
detectable 2a in THF. We find that the anion of triethyl
phosphonoacetate, produced via deprotonation by NaH in
anhydrous, ice-cold THF, readily reacts with Selectfluor1 to
give 2a, and also 3a. Either 2a or 3a can be the predominant
product depending on the equivalents of NaH used and the
excess of Selectfluor1 (Table 2). This method, therefore, can
be adjusted to obtain one of the products predominantly in a
single step. When one equivalent of NaH and 1.0–1.5 eq.
Selectfluor1 were used, triethyl fluorophosphonoacetate 2a
(40–50%) was cleanly formed, only a trace of triethyl
difluorophosphonoacetate 3a being detected (31P NMR) in
the reaction mixture. No side product derived from P–C
bond cleavage was observed (Table 2), and refluorination of
recovered 1a could potentially increase the yield to >70%.
On the other hand, with 2.5 eq. NaH and 3.0 eq.
Selectfluor1, triethyl difluorophosphonoacetate 3a was
the only fluorinated product (78%, by 31P NMR), the
remainder being the presumed phosphate compound 6
(dP = 0.2 ppm, ꢀ22%) derived from P–C cleavage as
observed with the FClO3/t-BuOK method. Pure triethyl
fluorophosphonoacetate 2a and triethyl difluorophospho-
noacetate 3a were obtained by adapting the isolation
procedures used in the FClO3 method.
Fluorination of product 2a competes with monofluorina-
tion of 1a, owing to the base equilibria present, and some 3a
is always formed (Scheme 1). Where both compounds may
be desired in comparable amount as has been the case in
some of our work, this feature is advantageous. The
extractive workup transfers residual chlorate salts to the
aqueous phase for harmless disposal and also readily
separates 2a from 3a. With the a-alkyl substituted substrate
5a, the yield of desired product is higher, as no difluoro
product is possible.
Several mechanisms have been proposed for fluorination
of anions derived from acidic methylene compounds by
FClO3. One mechanism involves attack of the carbanion on
fluorine [27–29]. Initial attack by enolate oxygen at chlorine
giving a cyclic intermediate or a transition state that
rearranges to make the new C–F bond has also been
proposed [30]. Steric and other arguments have been
opposed to this mechanism in specific cases [31].
As the Selectfluor1 molecule has two positive charges
and retains a single charge after fluorine atom transfer, both
unreacted Selectfluor1 and its byproduct are fairly soluble
Table 2
Fluorination of 1a with Selectfluor1. Effect of 1a:base:Selectfluor1 ratio on
product distributiona
Lapsed commercial availability (e.g. in North America)
of perchloryl fluoride, and its synthetic inaccessibility have
led to efforts to find an alternative ‘‘electrophilic fluorine’’
reagent by replacement of the ClO3 moiety of perchloryl
fluoride by a more docile leaving group. Thus, a-
fluorocarbonyl compounds have been made from enolates
reacting with CF3OF [32], F2/CF3CO2Na in Freon1 at
À75 8C [33] or XeF6-graphite [34]. None of these methods
have yet been applied to b-diphosphonates or b-phospho-
nocarboxylate esters to our knowledge. The use of
NaH (eq.) Selectfluor (eq.) %Conversion 2a (%)
3a (%)
1.0
1.0
1.3
2.2
2.5
1.0
1.5
1.5
3.0
3.0
46
51
46
Trace
51 (40)b Trace
56
38
11
0
12 (6)c
100
100
77 (12)c
78 (69)b(22)c
Based on 31P NMR.
Isolated yield.
a
b
c
Side product 6 derived from P–C cleavage of 3a.

1470
M.S. Marma et al. / Journal of Fluorine Chemistry 126 (2005) 1467–1475
Table 3
Fluorination of 4a with Selectfluor1. Effect of 4a:NaH:Selectfluor1 ratio
on product yield
CO–ethyl ester function, allowing one-pot preparation of
the triacids 2e, 3e, and 5e in good yields. Thus, inclusion of
an additional silylation step using iodotrimethylsilane to
convert the ethyl P,P-bis(trimethylsilyl) esters [2,17] into
tris(trimethylsilyl) esters or preliminary basic hydrolysis of
the C–O ester can be avoided [5]. The acids are hygroscopic
but are easily converted to stable (>1 year), crystalline
bis(dicyclohexylammonium) or pyridinium salts. A curious
property of the acid 3e is its tendency to turn black on
prolonged storage at room temperature. This behavior was
not observed with 2e under the same storage conditions, and
remains unexplained [47].
4a (eq.)
NaH (eq.)
Selectfluor (eq.)
%Yielda
1.0
1.0
1.1
1.3
1.5
1.5
90
97 (85)b
a
31P NMR yield.
b
Isolated yield.
in water; they can be readily removed by partitioning the
reaction mixture between water and CH2Cl2 or EtOAc. The
monofluorinated product (2a) is partially soluble in water, so
to minimize product loss during aqueous workup, a
minimum of water and excess organic solvent should be
used. When an excess of NaH is used to produce
difluorinated product 3a, undesired P–C bond cleavage is
reduced by running the reaction at lower temperature (0 8C).
In fluorination of 4a, the desired product 5a can be formed
very cleanly (97% conversion by 31P NMR) with no P–C
bond cleavage observed, and the product is readily purified
by distillation or chromatography. For this reaction, a slight
excess of NaH (1.3 eq.) and about 1.5 eq. Selectfluor1 were
required for complete fluorination (Table 3).
The second hydrolysis step can be averted by replacing
the H2O with ethanol or acetone containing a small amount
of H2O (Scheme 2). Under these conditions, the partial ethyl
esters 2c and 3c can be isolated in good yield. Compounds 2c
and 3c are readily handled as dicyclohexylammonium salts
(mono-salts are obtained, confirming that pK2 involves the
carboxylic acid group in the corresponding triacids 2e and
3e, which form di-salts).
In principle, the complementary carboxylic acid-phos-
phonate diesters should be available by careful alkaline
hydrolysis of the triesters, as demonstrated in the conversion
of 1a to 1d in 0.01 M NaOH (see experimental for detail).
However, the difluorinated triester showed a tendency to
decompose under these conditions.
Treatment of esters 2a, 3a and 5a with BTMS at 50 8C
gave the expected [25,26] ethyl P,P-bis(trimethylsilyl)
esters 2b, 3b and 5b in quantitative yield, conveniently
monitored by the resulting upfield 31P NMR shift of about
19 ppm (Table 5), or by observing the disappearance of the
POCH2CH3 proton resonances, as noted in other silyl-
dealkylations [6,25,26]. In agreement with a similar
finding for tetraalkyl mono- and difluoromethylenebispho-
sphonates [6], the electron deficient 2a and 3a display
somewhat attenuated reactivity in silyldealkylation by
BTMS, consistent with a phosphonium-like transition state
in this reaction. In our hands, the moderate increase in
temperature and recoverable excess of BTMS needed to
facilitate silyldealkylation of these electron-deficient
phosphonate esters resulted in a satisfactorily clean,
quantitative reaction. We showed previously [25,26] that
similar silyl esters can be isolated and fully characterized,
as is demonstrated here for 1b, but in preparing the other
a-fluoroacids described here these intermediates were
used without purification.
NMR data used in characterizing the compounds are
1
presented in Tables 4 and 5. The H NMR spectrum of 2a
(Table 4) manifests diastereotopic splitting of the
CH3CH2[PO] resonances, as expected. A generally similar
1H NMR spectral pattern is seen for 5a. The difluoro ester 3a,
lacking a chiral center, has only a single CH3CH2[PO]
methyl resonance.
Turning next to the 13C NMR data (Table 4), several
aspects can be noted. Firstly, the 13C d values for the a-
carbons in 2a and 3a show expected large downfield shifts
with increasing fluorine substitution, and the chemical shift
of the CH2[CO] carbons is a few ppm upfield of the CH2[PO]
carbons in both compounds. A small long-range 13C–31P
coupling (6 Hz) is observed for the –OCH2CH3[PO] and
–OCH2CH3[PO] carbon nuclei. The larger J value (193 Hz)
in the pair of doublets for CHFP in 2a is identified as JCF
rather than JCP (157 Hz) on the basis of comparison to
the13C NMR spectrum of 3a, where the different multiplicity
(CF2 versus CP) makes the assignment unambiguous. This
In contact with H2O at room temperature, the silyl esters
spontaneously hydrolyze to the corresponding phosphonic
acids, which on gentle warming of the solution (50 8C, 6 h)
cleanly undergo further hydrolysis of their remaining
reverses the assignment of JCP
in a related phosphonoacetate [48].
=
191 Hz made for CHFP
Scheme 2. Dealkylation pathways of triethyl fluorophosphonoacetates.

M.S. Marma et al. / Journal of Fluorine Chemistry 126 (2005) 1467–1475
1471
Table 4
a-Fluorophosphonoacetates: 1H and 13C NMR data
Compound
d
1H (CDCl3; J in Hz)
d
13C (CDCl3; J in Hz)
3
1.27 (t, JHH = 7.1, CH3[CO])
1
14.1 (q, JCH = 127, CH3[CO])
Et3FPAA (2a)
3
1.30, 1.31 (2td, JHH = 7, JPH = 0.6, 2CH3)
4
1
16.1 (qd, JCH = 128, JCP = 6, 2CH3[PO])
3
1
62.3 (t, JCH = 147, CH2[CO])
4.18 (m, 2CH2 [PO])
3
4.27 (2q, JHH = 7.1, CH2[CO])
3
64.2, 64.2 (td, JCH = 149, JCP = 6,2CH2[PO])
2
2
5.10 (dd, JFH = 47, JHP = 12, CHF)
2
1
1
1
85.7 (ddd, JCH = 313, JCF = 195, JCP = 157, CHF)
2
165.0 (dd, JCF = 22, JCP = 5, C O)
2
3
1.34 (t, JHH = 7.1, CH3[CO])
1
14.4 (q, JCH = 127, CH3[CO])
Et3F2PAA (3a)
3
4
1.36 (td, JHH = 7.1, JHP = 0.8, 2CH3[PO])
1
2
16.8 (qd, JCH = 126, JCP = 6, 2CH3[PO])
1
64.6 (t, JCH = 151, CH2[CO])
4.16 (m, 2CH2[PO])
3
4.25 (q, JHH = 7.15, CH2[CO])
1
66.2 (td, JCH = 150, JCP = 6, 2CH2[PO])
2
1
112.5 (td, JCF = 271, JCP = 202, CF2)
1
2
162.7 (td. JCF = 27, JCP = 18, CO)
2
3
1.12 (t, JHH = 7.1, CH3[CO])
1
13.9 (q, JCH = 127, CH3[CO])
Et3FPPA (5a)
3
1.14, 1.15 (2td, JHH = 7.1, JHP = 0.6,
4
1
16.3 (qd, JCH = 128, JCP = 6, 2CH3[PO])
3
3
1.72 (dd, JHF = 23, JHP = 15, FCCH3)
3
1
20.1 (qd, JCH = 132, JCF = 22, FCCH3)
2
1
62.1 (t, JCH = 148, CH2[CO])
4.03 (m, 2CH2[PO])
3
4.10 (q, JHH = 7.1, CH2[CO])
1
64.0 (td, JCH = 149, JCP = 16.7, 2CH2[PO])
2
1
1
92.9 (dd, JCF = 194, JCP = 168, FCCH3)
2
167.7 (dd. JCF = 23, JCP = 5, CO)
2
Table 5
a-Fluorophosphonoacetates: 31P and 19F NMR data (cf. refs. [2,3])
Compound
Solvent d
31P (J in Hz)
d
19F (J in Hz)
2
10.7 (ddp, JPF = 71.5, JPH = 12, JPH = 8)
2
3
2
2
Et3FPAA (2a)
Et3F2PAA (3a)
Et3FPPA (5a)
(TMS)2EtFPAA (2b)
EtFPAA (2c)a
EtF2PAA (3c)a
FPAA (2e)a
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
D2O
À214.7 (dd, JPF = 72, JFH = 47)
2
3
3.9 (tp, JPF = 96.4, JPH = 8)
2
À116.6 (d, JPF = 96.4)
2
3
2
3
13.8 (dqp, JPF = 84, JPH = 15,3JPH = 8)
À176.1 (dq, JPF = 84, JFH = 23
2
2
À7.5 (dd, JPF = 73, JPH = 12)
–
2
5.5 (dd, JPF = 63, JPH = 12)
2
2
2
À214.5 (dd, JPF = 64, JFH = 18)
2
0.86 (t, JPF = 79)
2
À122.5 (d, JPF = 79.5)
2
8.4 (dd, JPF = 69, JPH = 12)
2
2
2
À206.8 (dd, JPF = 68, JFH = 14)
2
8.6 (dd, JPF = 69, JPH = 14)
2
2 2
À207.1 (dd, JPF = 68, JFH = 15)
FPAA (2e)b
D2O
2
Et(TMS)2F2PAA (3b)
F2PAA (3e)a
CDCl3
D2O
À14.5 (t, JPF = 100)
–
2
4.1 (t, JPF = 91)
2
À116.3 (d, JPF = 90)
2
3.6 (t, JPF = 88)
2
F2PAA (3e)b
D2O
À118.4 (d, JPF = 90)
2
14.6 (dq, JPF = 82, JPH = 14.5)
3
FPPA (5e)a
D2O
–
a
DCHA salt.
b
Pyridinium salt.
The 31P NMR data (Table 5) for the product esters
indicate that the second fluorine substituent gives an upfield
shift (ca. 7 ppm). This shielding effect is also seen in
tetraethyl fluoromethylenebisphosphonates [6]. The 31P
chemical shift values for the product acid salts are pH
sensitive and thus are less exactly compared here, since the
sample pH was not adjusted.
fluorination of 4a provides a facile route to 5a. The new
procedure affords ready access to the a-fluoro phospho-
noacetic triacid derivatives 2e, 3e, 5e and the CO–Et
monoesters 2c and 3c. Details of convenient one-pot
preparations of the latter are provided, leading directly to
their stable pyridinium or DCHA salts.
The19FNMRdata(Table5)for2aand3amaybecorrelated
with the data for the corresponding tetraethyl a-fluorinated
methylenebisphosphonates [6]. In both sets of compounds,
inclusion of the second fluorine atom causes a downfield shift
of ca. 100 ppm, while 2JFP increases by about 23 Hz.
In conclusion, compared to FClO3/t-BuOK or /Na in
toluene, direct fluorination of 1a in THF and NaH with
Selectfluor1, using the procedures detailed here, possesses
important advantages of safety, selectivity and simplicity for
a practical one-step preparation of either 2a or 3a. Similar
2.1. Experimental
Triethyl phosphonoacetate and triethyl 2-phosphonopro-
pionate were purchased from Aldrich and distilled before
use. Potassium t-butoxide (t-BuOK) from the same vendor
was used immediately from a freshly opened bottle and
handled under N2. BTMS and Selectfluor1 (Aldrich) were
used as received. Dicyclohexylamine (Aldrich) was distilled
before use. Perchloryl fluoride was purchased from Ozark-
Mahoning Co., currently Ozark Fluorine Specialties (carries

1472
M.S. Marma et al. / Journal of Fluorine Chemistry 126 (2005) 1467–1475
the reagent in its catalog, but no longer supplies it).
Perchloryl fluoride is a powerful oxidant and it is essential to
follow exactly safe procedures in using it: for general
precautions, see previously cited references [6]. Apparatus
in contact with FClO3 was connected with Tygon tubing.
Ground-glass joints were lubricated with ‘‘Series 2s-25’’
halocarbon grease, and ‘‘KF-3’’ halocarbon oil was used in
gas bubblers; both materials were obtained from Halocarbon
Products Corp., Hackensack, NJ. Tetrahydrofuran (EMD)
was purified by distillation from Na. Other solvents were
also of analytical reagent grade and were used directly.
Glassware used in the fluorinations was dried overnight at
150 8C. Melting points were determined on a Mel-Temp or
Thomas-Hoover apparatus in capillary tubes and are
uncorrected. Proton (1H), carbon (13C), phosphorus (31P)
and fluorine (19F) NMR spectra were measured on a Bruker
AM-360 MHz or AC-250 MHz spectrometer. Chemical
shifts are reported relative to external TMS (1H), internal
CDCl3 [d = 77.0] (13C), external 85% H3PO4 (31P) or
external CFCl3 (19F). All chemical shifts upfield of the
reference are given as negative values. NMR data for
products described below are collected in Tables 4 (H,C) and
5 (P,F). Elemental analyses were performed by Galbraith
Laboratories. Note: until the toxicity of the a-fluoro
compounds described in this paper has been established,
they should be handled appropriately in view of the known
toxicity of fluoroacetic acid.
80% of the phosphorus-containing products; the remaining
20% was 1a (dP = 21 ppm) and a side product (6) with
dP = 0.2 ppm (s) was observed by 31P NMR.
2.3. Triethyl difluorophosphonoacetate 3a
The residue described above was partitioned between
hexane (200 mL) and 0.1 M NaHCO3 (5 Â 50 mL) and the
hexane extracts were dried (MgSO4). Removal of the solvent
by rotary evaporation at reduced pressure left 5.4 g pure
triethyl difluorophosphonoacetate (45%) which was vacuum
distilled to give a colorless oil, bp 66–67 8C (0.02 mm); TLC
(EtOAc:benzene, 2:1) Rf 0.46; NMR: H, C, P, F (Tables 4
and 5). Anal: found: C, 37.23; H, 5.97%. C8H15O5F2P
requires C, 36.93; H, 5.81%.
2.4. Triethyl fluorophosphonoacetate 2a
The bicarbonate fractions were combined and re-
extracted with chloroform (5 Â 50 mL). The chloroform
extracts were dried (MgSO4), and the solvent removed in
vacuo. 31P NMR of the residue showed a mixture (7.2 g) of
triethyl fluorophosphonoacetate (dP = 11.8 ppm) and
triethyl phosphonoacetate (dP = 21 ppm). The two com-
pounds could not be easily separated by fractional
distillation due to their similar boiling points. They were
obtained by flash chromatography on a 63 mm  457 mm
column of Kieselgel 60, 230–400 mesh, eluted with ethyl
acetate/benzene (2:1) (4 L) to yield twenty fractions.
Fractions 15–20 (1 g) contained starting material 1a; TLC
(EtOAc/benzene, 2:1) Rf 0.22. Fractions 5–13 were
combined to provide 3.9 g pure triethyl fluorophosphonoa-
cetate (36%), which was vacuum distilled to give a colorless
oil: bp 78–80 8C (0.01 mm); TLC (EtOAc/benzene, 2:1) Rf
0.37; NMR: H, C, P, F. (Tables 4 and 5); Anal: found: C,
39.79; H, 6.68%. C8H16O5FP requires C, 39.68; H, 6.66%.
2.2. Fluorination of triethyl phosphonoacetate
carbanion by perchloryl fluoride
A 2 L three-necked round-bottomed flask equipped with
an inlet gas bubbler attached to a subsurface gas addition tube,
a condenser connected to an outlet gas bubbler, and an
addition funnel was charged under N2 with 8.40 g
(74.8 mmol) t-BuOK in 400 mL toluene. The magnetically
stirred suspension was cooled to 5 8C (ice bath) and a solution
of 10.0 g (44.6 mmol) triethyl phosphonoacetate in 200 mL
dry toluene was added dropwise. As addition proceeded, the
mixture thickened into a slurry. It was allowed to warm to
10 8C and stirred vigorously while the inlet gas was changed
from N2 to perchloryl fluoride, using a 3-way stopcock. The
brownreactionmixture becameyellow andgraduallyclarified
as perchloryl fluoride was passed in at the maximal rate
consistent with total absorption, as determined by comparing
inlet and outlet gas bubblers, while the temperature was
maintained between 10 and 20 8C by occasional cooling with
an ice bath. When the outlet gas bubbler again became active
after approximately 50 min, flow was reduced three-fold and
then stopped when inlet and outlet bubbling rates were
equivalent. After flushing the apparatus with N2, the clear,
pale yellow reaction mixture was extracted with 2 Â 50 mL
portions of H2O. The toluene phase was dried (MgSO4) and
the solvent removed by rotary evaporation at reduced pressure
and50 8C. 31PNMRanalysisofthe residue(11 g)showedthat
2a (dP = 11.8 ppm) and 3a (dP = 4.0 ppm) constituted at least
2.5. Triethyl 2-fluoro-2-phosphonopropionate 5a from
perchloryl fluoride method
Triethyl 2-phosphonopropionate (8.50 g, 35.7 mmol) in
toluene (150 mL) was added under N2 to a well-stirred
solution of t-BuOK (4.4 g, 39 mmol) in toluene (300 mL) at
ice-bath temperature. The clear, brownish mixture was
allowed to warm to 10 8C and perchloryl fluoride was passed
in rapidly at 10–20 8C until the end point was evident as
described above (30 min). The resulting solution was
flushed with N2 and then extracted with H2O
(3 Â 15 mL). The toluene extracts were dried (MgSO4)
and the solvent removed in vacuo. 31P NMR analysis of the
residue showed that the desired product 5a (dP = 13.8 ppm)
made up 85% of the phosphorus-containing products; the
remaining 15% was accounted for by a side product
(dP = 0.2 ppm). The two compounds were easily isolated by
vacuum distillation. Triethyl 2-fluoro-2-phosphonopropio-
nate (7.13 g, 78% yield) was obtained as a colorless oil, bp

M.S. Marma et al. / Journal of Fluorine Chemistry 126 (2005) 1467–1475
1473
77–79 8C (0.01 mm). NMR: H, C, P, F. (Tables 4 and 5).
Anal: found: C, 42.41; H, 7.25%. C9H18O5FP requires C,
42.19; H, 7.08%.
2.8. 2-Fluoro-2-phosphonoproprionate 5a using
Selectfluor1
To 214 mg NaH (60% in oil, 5.35 mmol) in 6 mL dry
THF under N2, freshly distilled triethyl 2-phosphonopro-
prionate 4a (1.0 g, 4.19 mmol) was added dropwise (0 8C)
and the mixture stirred for 1 h, then for 1 h at room
temperature. Selectfluor1 (2.23 g, 6.29 mmol) was added
at once at 0 8C. After stirring for 1 h, the mixture was
brought to room temperature and stirring continued
overnight. 31P NMR showed clean conversion to the
fluorinated product 5a (97%) with no P–C bond cleavage
evident. The reaction was quenched by addition of 25 mL
aq. NH4Cl (5%). After extraction with CH2Cl2
(3 Â 100 mL), the combined organic phases were dried
(MgSO4), concentrated and chromatographed on silica gel
(EtOAc: CH2Cl2/9:1), Rf 0.52) giving 5a (0.91 g, 85%
2.6. Preparation of triethyl fluorophosphonate 2a using
Selectfluor1
To 185 mg NaH (4.6 mmol; 60% in oil) dispersed in
6 mL anhydrous THF under N2, 1.0 g triethyl phosphonoa-
cetate (4.5 mmol) was added dropwise at 0 8C. The reaction
mixture was stirred 30 min at the same temperature and an
additional hour at room temperature. The reaction was
recooled to 0 8C and Selectfluor1 (2.37 g, 6.75 mmoles)
was added at once. The reaction mixture was stirred for 1 h
with continued cooling followed by 4 h at room temperature.
31P NMR showed that triethyl a-fluorophosphonoacetate 2a
(dP = 10.7 ppm, d, 2JPF = 71.5 Hz, P–H decoupled) was the
main product (with a trace of difluorinated product 3a,
1
yield) as a colorless oil, characterized by H, 13C and 31P
2
dP = 3.5 ppm, t, JPF = 95.1 Hz, P–H decoupled) in the
NMR (Tables 4 and 5).
reaction mixture; the remainder was starting material
(dP = 20.5 ppm, s, P–H decoupled). The reaction mixture
was then treated with 25 mL aq. NH4Cl (5%) and extracted
with EtOAc (3 Â 100 mL). The EtOAc fractions were
combined and dried over MgSO4, concentrated under
vacuum, and the residual product was purified by silica
gel column chromatography (EtOAc: toluene/5:1, Rf 0.53).
The product obtained by chromatography contained a trace
of difluoro derivative 3a, which was removed by the
following procedure: the sample was dissolved in hexane
(25 mL) and extracted with 0.1 M NaHCO3 solution
(3 Â 100 mL), leaving the 3a in the hexane phase. The
aqueous phase was then extracted with CH2Cl2
(5 Â 100 mL). After drying (MgSO4) and evaporation of
solution, pure 2a was obtained as a colorless oil (0.42 g, 40%
2.9. Ethyl P,P-bis(trimethylsilyl) phosphonoacetate 1b
Bromotrimethylsilane (2.26 g, 14.8 mmol) was added
dropwise with stirring under N2 to triethyl phosphonoacetate
(1.23 g, 5.48 mmol). The reaction progress was readily
followed by 31P or 1H NMR. After 6 h at 50 8C, ethyl
bromide and excess silylating reagent was removed in vacuo
to leave the product (100% by 31P NMR), which was
vacuum distilled to give a colorless oil, bp 70–71 8C
(0.02 mm); 31P NMR (CDCl3) d = 1.2 ppm (t,
2JPH = 22.5 Hz). HR-MS: required for C10H25O5PSi2:
312.099; found (molecular ion, m/z): 312.098.
2.10. Ethyl P,P-bis(trimethylsilyl)
fluorophosphonoacetate 2b
1
yield). The product was characterized by H, 13C and 31P
NMR (Tables 4 and 5).
In a similar reaction, bromotrimethylsilane (1.26 g,
8.2 mmol) was added dropwise with stirring under N2 to
triethyl fluorophosphonoacetate (0.50 g, 2.1 mmol). At
50 8C after 6 h, rotary evaporation at reduced pressure gave
0.68 g product (100% by 31P NMR). NMR: P, F (Table 5).
The compound was further characterized by conversion to
the acid 2c (see below).
2.7. Preparation of triethyl difluorophosphonoacetate
3a using Selectfluor1
To 223.0 mg NaH (60% in oil, 5.6 mmol) dispersed in
5 mL dry THF under N2, freshly distilled triethyl phospho-
noacetate (0.5 g, 2.2 mmol) was added dropwise at 0 8C and
stirred for 1 h, followed by 1 h at room temperature. The
reaction mixture was recooled to 0 8C and Selectfluor1
(2.37 g, 6.69 mmol) was added in two portions. After stirring
for 1 h at 0 8C and then 3 h at room temperature, the 31P NMR
of the reaction mixture showed complete conversion of the
starting material 1a to triethyl difluorophosphonoacetate 3a
(dP = 3.4 ppm, t, J = 96.4 Hz, P-Hdecoupled, 78%) and aside
product 6 (22%). The reaction mixture was quenched by the
addition of 0.1 M NaHCO3 (100 mL) and difluorinated
product 3a was then extracted by hexane (3 Â 100 mL). After
drying on MgSO4, the solvent was evaporated under vacuo to
obtain3aasclear oil(398 mg, 69%yield), NMRasinTables4
and 5.
2.11. Ethyl fluorophosphonoacetate 2c
(dicyclohexylammonium salt)
To 0.34 g (1.0 mmol) of 2b under N2 was added with
stirring 10 mL of ethanol containing 20 mL (1.1 mmol) H2O.
After 3 h at room temperature, the reaction mixture was
evaporatedatreducedpressuretogivethediacid(100%by31
P
NMR) which was isolated as its dicyclohexylammonium salt.
Forthis purpose, thereactionproduct was dissolved inethanol
and excess dicyclohexylamine added. The precipitated salt
(0.12 g, 33%) was recrystallized successively from ethanol/
acetone andethanol:mp >225 8C, NMR: P, F (Table 5). Anal:

1474
M.S. Marma et al. / Journal of Fluorine Chemistry 126 (2005) 1467–1475
found: C, 51.63; H, 8.34; N, 3.71%. C16H31O5FNP.1/4 H2O
requires C, 51.67; H, 8.54; N, 3.77%.
9.17; N, 5.20%. Pyridinium salt, prepared from 3a as
described above, mp: 117–119 8C (sintered). NMR: P, F
(Table 5). Anal: found: C, 33.23; H, 3.25; N, 5.66%.
C7H8O5F2NP requires C, 32.96; H, 3.16; N, 5.49%.
2.12. Fluorophosphonoacetic acid 2e
(bis(dicyclohexylammonium) and pyridinium salts)
2.16. 2-Fluoro-2-phosphonopropionic acid 5e
(bis(dicyclohexylammonium salt))
The silyl ester 2b (0.34 g, 1.0 mmol) was stirred with
10 mL of H2O. After 6 h at 50 8C, the reaction mixture was
evaporated to dryness at reduced pressure to give the triacid
(100% by 31P NMR) which was characterized as the
bis(dicyclohexylammonium) salt, prepared as described
above and recrystallized successively from ethanol/acetone
and absolute ethanol: mp 183–185 8C (softens at 168 8C).
NMR: P, F (Table 5). Anal: found: C, 59.74; H, 9.93; N,
5.11%. C26H50O5FN2P requires C, 59.98; H, 9.68; N, 5.38%.
Alternatively, ester 2a (100 mg, 0.413 mmol) was
refluxed overnight in conc. HCl; the syrupy residue left
after evaporation in vacuo was treated with 2–3 times excess
dry pyridine and the resultant salt recrystallized from
methanol and dried 12 h at 60 8C: 93.3 mg (96%), mp 179–
180 8C. NMR: P, F (Table 5). Anal: found: C, 35.39; H, 3.71;
N, 5.99%. C7H8O5FNP requires C 35.61; H 3.41; N 5.93%.
Treatment of 5a with excess bromotrimethylsilane
followed by aqueous work up as described above gave
the desired product (90%), characterized as the bis(dicy-
clohexylammonium) salt, mp 198–199 8C. NMR:
(Table 5). Anal: found: C, 58.50; H, 10.01; N, 4.95%.
P
C27H52O5FN2P.H2O requires C, 58.67; H, 9.85; N, 5.07%.
2.17. P,P-Diethyl phosphonoacetic acid 1d
Triethyl phosphonoacetate (1.0 g, 4.5 mmol) was added
to a solution of 0.01 M sodium hydroxide (20 mL). Reaction
1
progress was followed by H NMR. After 8 h at 50 8C, the
solution was passed into a column of Dowex 50 (H+)
(30 mL) and eluted with H2O (50 mL). The eluate was
evaporated to dryness under reduced pressure to yield the
desired product as a viscous colorless liquid (0.80 g, 87%).
31P NMR (D2O): dP = 22 ppm(m). Anal: found: C, 35.15; H,
6.84%. C6H13PO5Á1/2 H2O requires C, 35.13; H, 6.88%.
2.13. Ethyl P,P-bis(trimethylsilyl)
difluorophosphonoacetate 3b
Bromotrimethylsilane (1.17 g, 7.64 mmol) was added
dropwise under N2 with stirring to triethyl difluoropho-
sphonoacetate (0.25 g, 0.96 mmol). After 6 h at 50 8C,
evaporation under reduced pressure left the product (0.32 g,
100% by 31P NMR). NMR: P, F (Table 5). Further
characterization was carried out by conversion to the
corresponding acid (described below).
Acknowledgements
This research was supported by the National Institutes of
Health (AI-21871), a Faculty Research Innovation Fund
award from the University of Southern California, and
Procter & Gamble Pharmaceuticals.
2.14. Ethyl difluorophosphonoacetate 3c
(dicyclohexylammonium salt)
References
To 0.16 g (0.46 mmol) of 3b under N2 was added with
stirring 10 mL of ethanol containing 10 mL (0.55 mmol)
H2O. After 3 h at room temperature, the reaction mixture
was evaporated to dryness at reduced pressure to give the
diacid (100% by 31P NMR). The dicyclohexylammonium
salt was prepared and recrystallized as described above:
0.2 g, mp >225 8C. NMR: P, F (Table 5). Anal: found: C,
50.16; H, 7.73; N, 3.53%. C16H30O5F2NP requires C, 49.87;
H, 7.85; N, 3.63%.
[1] C.E. McKenna, L.A. Khawli, Phosphorus Sulfur 18 (1983) 483.
[2] D.J. Burton, L.G. Sprague, D.J. Pietrzyk, S.H. Edelmuth, J. Org.
Chem. 49 (1984) 3437–3438.
[3] G.M. Blackburn, D. Brown, S.J. Martin, J. Chem. Res., Synop. (1985)
92–93.
[4] R.V. Talanian, N.C. Brown, C.E. McKenna, T.G. Ye, J.N. Levy, G.E.
Wright, Biochemistry 28 (1989) 8270–8274.
[5] C.J. Hamilton, S.M. Roberts, J. Chem. Soc., Perkin Trans. 1 (1999)
1051–1056.
[6] C.E. McKenna, P.-D. Shen, J. Org. Chem. 46 (1981) 4573–4576.
[7] G.M. Blackburn, D.A. England, F. Kolkmann, J. Chem. Soc., Chem.
Comm. (1981) 930–932.
2.15. Difluorophosphonoacetic acid 3e
(bis(dicyclohexylammonium) and pyridinium salts)
[8] D.B. Berkowitz, M. Bose, J. Fluorine Chem. 112 (2001) 13–33.
[9] S.M. Miller, Biochemistry 34 (1995) 13066–13073.
[10] C.E. McKenna, L.A. Khawli, J. Org. Chem. 51 (1986) 5467–5470.
[11] C.E. McKenna, L.A. Khawli, A. Bapat, V. Harutunian, Y.C. Cheng,
Biochem. Pharmacol. 36 (1987) 3103–3106.
The silyl ester (3b) (0.16 g, 0.46 mmol) was stirred in
10 mL of H2O at 50 8C for 6 h. Evaporation under reduced
pressure gave the triacid (100%). The bis(dicyclohexylam-
monium) salt was prepared and recrystallized as described
above: mp 224–226 8C. NMR: P, F. Anal: found: C, 58.22;
H, 8.96; N, 5.36%. C26H49O5F2N2P requires C, 57.98; H,
[12] A. Thenappan, D.J. Burton, J. Org. Chem. 55 (1990) 4639–4642.
[13] P.W. Collins, S.W. Kramer, G.W. Gullikson, J. Med. Chem. 30 (1987)
1952–1955.
[14] H. Machleidt, R. Wessendorf, Ann. Chem. 674 (1964) 1–10.

M.S. Marma et al. / Journal of Fluorine Chemistry 126 (2005) 1467–1475
1475
[15] A.V. Fokin, V.I. Zimin, Y.N. Studnev, A.I. Rapkin, Zh. Org. Khim. 7
(1971) 249–251.
[32] W.J. Middleton, E.M. Bingham, J. Am. Chem. Soc. 102 (1980) 4845–
4846.
[16] X. Zhang, W. Qiu, D.J. Burton, Tetrahedron Lett. 40 (1999) 2681–2684.
[17] D.J. Burton, L.G. Sprague, J. Org. Chem. 53 (1988) 1523–1527.
[18] C.E. McKenna, N.D. Leswara, P.-D. Shen, Fed. Proc. 41 (1982) 860.
[19] C.E. McKenna, N.D. Leswara, I. Yi, Phosphorus Sulfur 18 (1983) 487.
[20] G.M. Blackburn, F. Eckstein, D.E. Kent, T.D. Perree, Nucleos.
Nucleot. 4 (1985) 165–167.
[33] S. Rozen, Y. Menahem, Tetrahedron Lett. (1979) 725–728.
[34] S.S. Yemul, H.B. Kagan, R. Setton, Tetrahedron Lett. 21 (1980) 277–
280.
[35] G.M. Blackburn, D.E. Kent, J. Chem. Soc., Perkin Trans. 1 (1986)
913–917.
[36] J. Ichihara, T. Matsuo, T. Hanafusa, T. Ando, J. Chem. Soc., Chem.
Comm. (1986) 793–794.
[21] G.M. Blackburn, M.J. Guo, Nucleos. Nucleot. 10 (1991) 549–551.
[22] B.I. Martynov, E.A. Shirokova, M.V. Jasko, L.S. Victorova, A.A.
Krayevsky, FEBS Lett. 410 (1997) 423–427.
[37] J.H. Clark, A.J. Hyde, D.K. Smith, J. Chem. Soc., Chem. Comm.
(1986) 791–793.
[23] A.L. Khandazhinskaya, E.A. Shirokova, Y.S. Skoblov, L.S. Victorova,
L.Y. Goryunova, R.S. Beabealashvilli, T.R. Pronyaeva, N.V. Fedyuk,
V.V. Zolin, A.G. Pokrovsky, M.K. Kukhanova, J. Med. Chem. 45
(2002) 1284–1291.
[38] R.E. Banks, G.E. Williamson, Chem. Ind. (London) (1964) 1864–
1865.
[39] G.S. Lal, G.P. Pez, R.G. Syvret, Chem. Rev. 96 (1996) 1737–
1755.
[24] G. Wang, N. Boyle, F. Chen, V. Rajappan, P. Fagan, J.L. Brooks, T.
Hurd, J.M. Leeds, V.K. Rajwanshi, Y. Jin, M. Prhavc, T.W. Bruice,
P.D. Cook, J. Med. Chem. 47 (2004) 6902–6913.
[40] R.E. Banks, J. Fluorine Chem. 87 (1998) 1–17.
[41] S.T. Purrington, W.A. Jones, J. Org. Chem. 48 (1983) 761–762.
[42] W.E. Barnette, J. Am. Chem. Soc. 106 (1984) 452–454.
[43] T. Umemoto, K. Tomita, Tetrahedron Lett. 27 (1986) 3271–3274.
[44] R.E. Banks, S.N. Mohialdin-Khaffaf, G.S. Lal, I. Sharif, R.G. Syvret,
J. Chem. Soc., Chem. Comm. (1992) 595–596.
[45] R.P. Singh, J.M. Shreeve, Acc. Chem. Res. 37 (2004) 31–44.
[46] G.S. Lal, J. Org. Chem. 58 (1993) 2791–2796.
[47] We have seen a similar change in samples of difluoromethylenebi-
sphosphonic acid stored over a long period of time: C.E. McKenna,
P.D. Shen, unpublished observation.
[25] C.E. McKenna, J. Schmidhauser, J. Chem. Soc., Chem. Comm. (1979)
739.
[26] C.E. McKenna, M.T. Higa, N.H. Cheung, M.C. McKenna, Tetrahe-
dron Lett. (1977) 155–158.
[27] J.P. Freeman, J. Am. Chem. Soc. 82 (1960) 3869–3873.
[28] J.F. Liebman, B.B. Jarvis, J. Fluorine Chem. 5 (1975) 41–54.
[29] R.H. Hesse, Isr. J. Chem. 17 (1978) 60–70.
[30] W.A. Sheppard, Tetrahedron Lett. (1969) 83–84.
[31] I.V. Vigalok, Y.A. Fedotov, A.A. Vigalok, Y.A. Levin, Zh. Org. Khim.
15 (1979) 407–411.
[48] G. Etemad Moghadam, J. Seyden Penne, Tetrahedron 40 (1984) 5153–
5166.