Selective synthesis of α-fluoro-β-keto-and α-fluoro- β-aminophosphonates via electrophilic fluorination by selectfluor

Article abstract of DOI:10.1021/jo102276y

A series of α-mono-and α,α-difluoro-β- ketophosphonates were synthesized in moderate to good yields with excellent selectivities via electrophilic fluorination by Selectfluor. Subsequently, synthetic potential of the obtained α-monofluoro-β-ketophosphonates was demonstrated by their application in synthesis of α-monofluoro-β- aminophosphonates, useful building blocks in the preparation of phosphapeptides.

Full text of DOI:10.1021/jo102276y

pubs.acs.org/joc
physicochemical and biological properties of the molecules
Selective Synthesis of r-Fluoro-β-keto- and
r-Fluoro-β-aminophosphonates via Electrophilic
Fluorination by Selectfluor
and impact and utilization of fluorine span areas as diverse as
pharmaceuticals, agrochemicals, and polymers.2 In particu-
lar, interest in fluorine substitution of organic groups at-
tached to phosphorus stems from the possible effect of such
substitution on physical, chemical, and biological properties
of the resulting fluorinated phosphonates.3 Additionally, it is
worth noting, that the union of fluorine and phosphorus has
natural origin.4 As a result, it is desirable to devise novel
methods to allow easy access to fluoro-containing phospho-
nates in view of their great utility, and thus, the development
of selective procedures producing exclusively mono- or di-
fluorinated products would well serve this purpose.
Kinga Radwan-Olszewska,*,†,‡ Francisco Palacios,‡ and
Pawel Kafarski†
†Department of Bioorganic Chemistry,
Wroclaw University of Technology,
Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland, and
‡Department of Organic Chemistry,
University of the Basque Country, Apartado 450,
01080 Vitoria, Spain
Fluorination of phosphonates is not a trivial issue and
usually requires complex chemistry based on scarce synthetic
precursors and demanding reaction conditions.5 Recently, a
number of new fluorinating agents appeared, especially elec-
trophilic agents with an N-F structure, to introduce fluorine
atom into organic molecules and especially Selectfluor (1-
chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-
(tetrafluoroborate)) began to gain popularity as an excep-
tionally stable, virtually nonhydroscopic crystalline solid
and inexpensive electrophilic fluorinating agent.6 To the best
of our knowledge, there are only a few examples in the lite-
rature dealing with the application of this reagent for the
preparation of fluorinated-β-ketophosphonates. Hamilton
et al. and later on Marma et al. have reported the synthesis of
various R-fluorinated phosphonoacetate derivatives via elec-
trophilic fluorination by Selectfluor however, with poor
yields in range of 17% and 40-50%, respectively.7 Later on,
Selectfluor was used by Landame and co-workers for pre-
paration of functionalized dibenzyl R,R-difloromethylene-
β-ketophosphonates (40-60%), although the monofluori-
nated products were obtained in minor amounts (5-10%).8
Recently, Cox et al. have used Selectfluor for the preparation
of inhibitors of bacterial aspartate semialdehyde dehydro-
genase, containing R-fluoro-β-ketophosphonate unit.9 The
kinga.radwan-pytlewska@pwr.wroc.pl
Received November 15, 2010
A series of R-mono- and R,R-difluoro-β-ketophospho-
nates were synthesized in moderate to good yields with
excellent selectivities via electrophilic fluorination by Se-
lectfluor. Subsequently, synthetic potential of the obtained
R-monofluoro-β-ketophosphonates was demonstrated
by their application in synthesis of R-monofluoro-
β-aminophosphonates, useful building blocks in the pre-
paration of phosphapeptides.
As phosphorus analogues of natural aminocarboxylic
acids, the R- and β-aminophosphonic acids and their phos-
phonate esters exhibit a variety of intriguing biological
properties, and thus they have found diverse applications
in many areas of modern medicine and agriculture.1 On the
other hand, the introduction of the fluorine atom is often
adopted as a measure to usher in great changes in the
(3) (a) McKenna, C. E.; Shen, P. D. J. Org. Chem. 1981, 46, 4573–4576.
(b) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J. Chem. Soc., Perkin
Trans. 1 1984, 1119–1125. (c) Jakeman, D. L.; Ivory, A. J.; Willamson, M. P.;
Blackburn, G. M. J. Med. Chem. 1998, 41, 4439–4452. (d) Berkowitz, D. B.;
Bose, M. J. Fluorine Chem. 2001, 112, 13–33.
(4) (a) Cobb, L. S.; Deng, H.; Hamilton, J. T. G.; McGlinchey, R. P.;
O’Hagan, D. Chem. Commun. 2004, 7, 592–593. (b) O’Hagan, D. J. Fluorine
Chem. 2006, 127, 1479–1483. (c) Onega, M. O.; Domarkas, J.; Deng, H.;
Schweiger, L. F.; Smith, T. A. D.; Welch, A. E.; Plisson, C.; Gee, A. D.;
OHagan, D. Chem. Commun. 2010, 46, 139–141.
(5) For recent reviews, see: (a) Romanenko, V. D.; Kukhar, V. R. Chem.
Rev. 2006, 106, 3868–3935. (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108,
PR1–PR43. (c) Bobbio, C.; Gouverneur, V. Org. Biomol. Chem. 2006, 2065–
2075. (d) Coutrot, P.; Grison, C. Tetrahedron Lett. 1988, 29, 2655–2658.
(6) For reviews, see: (a) Banks, R. E. J. Fluorine. Chem. 1998, 87, 1–17. (b)
Nyfeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H.
Angew. Chem., Int. Ed. 2005, 44, 192–212. (c) Vincent, S. P.; Burkart, M. D.;
Tsai, C. Y.; Zhang, Z.; Wong, C. H. J. Org. Chem. 1999, 64, 5264–5279.
(7) (a) Hamilton, C. J.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1
1999, 1051–1056. (b) Marma, M. S.; Khawli, L. A.; Harutunian, V.;
Kashemirov, B. A.; McKenna, Ch. E. J. Fluorine Chem. 2005, 126, 1467–
1475.
(1) (a) Aminophosphonic and Aminophosphinic Acids; Kukhar, V. P.,
Hudson, H. R., Eds.; John Wiley & Sons: Chichester, 2000. For a compre-
hensive review, see: (b) Ordonez, M.; Rojas-Cabrera, H.; Cativiela, C.
Tetrahedron 2009, 65, 17–49. (c) Palacios, F.; Alonso, C.; de los Santos, M.
Chem. Rev. 2005, 105, 899–931. (d) Van der Jeught, S.; Stevens, Ch. V. Chem.
Rev. 2009, 109, 2672–2702. (e) Grembecka, J.; Mucha, A.; Cierpicki, T.;
Kafarski, P. J. Med. Chem. 2003, 46, 2641–2655. (f) Kafarski, P.; Lejczak, B.
Cur. Med. Chem: Anti-Cancer Agents 2001, 1, 301–312. (g) Grembecka, J.;
Kafarski, P. Mini-Rev. Med. Chem. 2001, 1, 133–144.
(2) (a) Modern Fluoroorganic Chemsitry: Synthesis, Reactivity, Applica-
tions; Kirch, P., Ed.; Wiley-VCH: Weinheim, 2004. (b) Muller, K.; Faeh, Ch.;
Diederich, F. Science 2007, 317, 1881–1886. (c) O’Hagan, D. Chem. Soc. Rev.
2008, 37, 308–319. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320–330. (e) Gouverneur, V. Science 2009, 325,
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(8) Landame, S.; Willson, M.; Perie, J. Eur. J. Org. Chem. 2002, 2640–
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(9) Cox, R. J.; Gibson, J. S.; Hadfield, A. T. ChemBioChem. 2005, 6,
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1170 J. Org. Chem. 2011, 76, 1170–1173
Published on Web 01/18/2011
DOI: 10.1021/jo102276y
r
2011 American Chemical Society

Radwan-Olszewska et al.
JOCNote
TABLE 1. Effect of Amount of Selectfluor and Additives on the
TABLE 2. Scope of the Electrophilic Fluorination of β-Ketophospho-
nates 1a-d by Selectfluora
Fluorination of β-Ketophosphonate 1aa
Selectfluor
(equiv)
2b (%)
3b (%)
entry base
solvent
1ab (%) 2ab (%) 3ab (%)
entry
substrate
Selectfluor (equiv)
2a (65)b
2b (62)b
2c (40)b
2d (50)b
2a (-)
3a (-)
1
2
3
4
5
6
7
8
NaH
LDA
none
none
none
none
none
none
1
1
1
2
2
2
4
6
THF
THF
CH3CN 1a (70)
CH3CN 1a (0)
THF
DMF
CH3CN 1a (0)
CH3CN 1a (0)
1a (0)c
2a (31)c 3a (69)c
1
2
3
4
5
6
7
8
1a, R = Ph
2
2
2
2
6
6
6
6
1a (100)c 2a (-)c
3a (-)c
3a (0)
3a (<5)
1b, R = CH3
1c, R = EtO2C
1d, R = CF3
1a, R = Ph
1b, R = CH3
1c, R = EtO2C
1d, R = CF3
3b (-)
2a (30)
2a (95)
2a (<5) 3a (0)
3c (-)
3d (-)
3a (45)b
3b (43) b
3c (40) b
3d (42) b
1a (95)
1a (90)
2a (10)
2a (35)
2a (<5) 3a (95)
3a (0)
2b (-)
3a (65)
2c (--)
2d (--)
aReactions were carried out using 1 mmol of 1a in 20 mL of solvent
at reflux for 24 h. No reaction was observed at room temperature.
bSelectivity of the fluorination was established on the basis of the
integration of signals in the 31P NMR spectra of crude reaction mixture.
cDeprotonation of 1a with base was done at 0 °C followed by addition of
Selectfluor; next the reaction was stirred at room temperature for 12 h.
aReactions were carried out using 1 mmol of 1 in 20 mL of CH3CN at
80 °C for 24 h. bIsolated yield of purified product after chromatography.
Values are an average of three experiments.
TABLE 3. Electrophilic Fluorination of Cyclic β-Ketophosphonates by
Selectfluora
SCHEME 1. Postulated Resonance Structure of Selectfluor
desired R- monofluoro- and R,R-difluorophosphonate deriv-
atives were obtained, after chromatographic separation,
with 50% and 16% yield, respectively, along with unreacted
starting material (20%). On the basis of these studies and as a
part of our continued interest in the synthesis of biologically
active phosphonates, we reasoned that fluorinated β-keto-
phosphonates may be accessible in selective fashion through
electrophilic fluorination by Selectfluor. Herein, we report
our results with this strategy.
Initially, the electrophilic fluorination by Selectfluor of
β-ketophosphonate 1a, as model substrate, was investigated.
The screening of the quantity of the fluorinating agent
revealed a pronounced effect on the selectivity of the reac-
tion. To our satisfaction, it was found that the use of a 2-fold
excess of Selectfluor leads selectively to monofluorinated
product (Table 1, entry 4), whereas the application of 6-fold
excess leads exclusively to difluorinated compound (Table 1,
entry 8). Knowing that the reactivity of the Selectfluor can be
strongly modulated by all the reaction parameters, especially
solvent system and the temperature, we carried out an
extensive screening of the reaction conditions. Screening of
several solvents revealed that CH3CN was the solvent of
choice (Table 1, entries 4-6). Reaction with 1 equiv of
fluorinating agent resulted in formation of monofluorinated
product, albeit accompanied by large amount of starting
material 1a (Table 1, entry 3). The use of 4 equiv of Select-
fluor led to formation of a mixture of mono- and difluori-
nated products (Table 1, entry 7). Also, experiments of
fluorination by Selectfluor in the presence of a base were
performed (Table 1, entries 1 and 2), which is the usual
protocol described in the literature.8,9 In the case were LDA
was used (Table 1, entry 2), fluorination did not take
place and starting material was recovered. The use of NaH
aReactions were carried out using 1 mmol of 1e,f in 20 mL of CH3CN
at 80 °C for 24 h. Isolated yield of purified product after chromatog-
raphy. Values are an average of three experiments.
b
(Table 1, entry 1) gave a mixture of mono- and difluorinated
products.
The mechanism of electrophilic fluorination of β-ketophos-
phonates is believed to involve an enolate interme-
diate resulting from deprotonation of β-ketophosphonate
moiety by a base.8,9 The fluorination method we report here
however, does not require the presence of additional base
and this fact caused us to postulate that the Selectfluor itself
play a role of a base as a result of its original structure that
involves 1,4-diazabicyclo[2.2.2]octane (DABCO), known to
be a strong base (Scheme 1).6b,10 That is why the presence of
1 equiv of Selectfluor is not enough to force the fluorination
reaction to proceed to completion and a lot of starting
material remains unreacted (Table 1, entry 3). In turn, with 2
equiv, total conversion of starting material into the selectively
(10) Caravano, A.; Dohi, H.; Sinay, P.; Vincent, S. P. Chem.;Eur. J.
2006, 12, 3114–3123.
J. Org. Chem. Vol. 76, No. 4, 2011 1171

Radwan-Olszewska et al.
JOCNote
SCHEME 2. Preparation of R-Monofluorinated β-Ketophosphonates 7
monofluorinated product is obtained (Table 1, entry 4).
When 4 equiv of fluorinating agent (Table 1, entry 7) is used,
the difluorinated product appears, this is presumably be-
cause the monofluorinated product is more acidic than the
starting material and deprotonates and fluorinates a second
time to finally yield selectively difluorinated β-ketophospho-
nate when 6 equiv. of Selectfluor is added (Table 1, entry 8).
Subsequently, a selected spectrum of β-ketophosphonates
was examined to test the scope of the presented protocol
(Table 2). Different aromatic-, aliphatic-, ester-, and trifluoro-
methyl-substituted β-ketophosphonates were tolerated under
the presented, optimized reaction conditions. Pure mono- and
difluorinated β-ketophosphonates 2a-d (Table 2, entries 1-4)
and 3a-d (Table 2, entries 5-8) were selectively obtained in
moderate to good yields.
the R-fluorinated-β-oximes 4. All attempts to directly reduce
oximes 4 to amines 7 using known literature procedures failed
in our case.12 Oximes 4 were, therefore, transformed into the
corresponding p-toluenesulfonyloximes 5 by reaction with
p-toluenesulfonyl chloride in pyridine and, subsequently, re-
duction by means of NaBH4 to afford the desired R-fluoro-
β-aminophosphonates 7 with acceptable yields (Scheme 2). It
is noteworthy that oximes 4 and p-toluenesulfonyloxime 5
were obtained as a mixture of E and Z stereoisomers. By
analogy with our previous works, both stereoisomers could be
easily distinguished using 31P NMR spectroscopy where the
E stereoisomer presented an upfield and Z stereoisomer a
downfield signals respectively.13 In the second, successful
strategy, the desired R-fluorinated β-aminophosphonates 7
were obtained with good yields by catalytic hydrogenation
of a crude mixture composed of R-fluoro-β-iminophospho-
nate 6 and R-fluoro-β-enaminophosphonate 60 due to
existence of such a tautomeric equilibrium.14 The presence
of both tautomeric forms was confirmed by NMR analysis
and by comparison of the obtained data in the literature
values.15 The 6/60 mixture was produced, in almost quan-
titative yield, by simple condensation of corresponding R-
fluoro-β-ketophosphonates 2 with benzylamine in refluxing
toluene using a Dean-Stark apparatus.
In conclusion, we have developed an efficient and selective
protocol for the synthesis of a palette of R-monofluoro- and
R,R-difluoro-β-ketophosphonates via electrophilic fluorina-
tion by Selectfluor. This method is featured with relatively
mild reaction conditions, simple operation, good substrate
scope, and excellent selectivity. The synthetic utility of the ob-
tained R-monofluoro-β-ketophosphonates was demonstrated
by efficient preparation of R-monofluoro-β-aminophospho-
nates, compounds otherwise difficult to obtain, and useful
building blocks in the synthesis of phosphapeptides.
Notably, cyclic β-ketophosphonates 1e,f also proved to be
suitable substrates for the electrophilic fluorination by Se-
lectfluor (Table 3, entries 1 and 2), giving the corresponding
fluorinated products 2e and 2f in 60% and 56% yield,
respectively.
In continuation, we examined the synthetic utility of the
obtained fluorinated-β-ketophosphonates as starting materials
in the preparation R-fluoro-β-aminophosphonates. Although
it is well-known that monofluorinated aminophosphonates are
better mimics of natural phosphonates with matched pKa
values,3 their synthesis is scarcely described in the literature.11
Development of new protocols leading to those derivatives
is therefore, especially desirable. Here we present two alter-
native synthetic pathways leading to R-fluoro-β-aminopho-
sphonates 7 using R-fluoro-β-ketophosphonates 2 as sub-
strates (Scheme 2). In the first approach, the synthesis of
R-fluoro-β-aminophosphonates 7 was accomplished by a
simple three-step protocol involving in the first step condensa-
tion of hydroxylamine hydrochloride with appropriate R-
fluoro-β-ketophosphonate 2 in the presence of Et3N to obtain
(12) Reduction of oximes 4 to amines 7 was attempted using the following
literature protocols: (a) Herscovici, J.; Ergon, M. J.; Antonakis, K. J. Chem.
Soc., Perkin Trans. 1, 1988, 5, 1219-1226 (NaBH4-NiCl2 and NaBH4-
MoO3 systems). (b) Hammond, N.; Koumi, P.; Langley, G. J.; Lowe, A.;
Brown, T. Org. Biomol. Chem., 2007, 5, 1878-1885 (Pd/C, H2-glacial
AcOH). (c) Abiraj, K.; Gowda, D. C. Synth. Commun., 2004, 34, 599-605
(Mg/HCOONH4). (d) Leeds, J. P.; Kirst, K. A. Synth. Commun., 1988, 18,
777-782 (TiCl3/NaBH3CN). (e) Hoffman, C.; Tanke, R. S.; Miller, M. J.
J. Org. Chem., 1989, 54, 3750-3752 (TiCl3/NaBH4).
(11) For synthesis of fluorinated aminophosphonates, see: (a) Berkowitz,
D. B.; Eggen, M. J.; Shen, Q.; Shoemaker, R. K. J. Org. Chem. 1996, 61,
4666–4675. (b) Berkowitz, D. B.; Shen, Q.; Maeng, J. H. Tetrahedron
Lett. 1994, 35, 6445–6448. (c) Otaka, A.; Mitsuyama, E.; Kinoshita, T.;
Tamamura, H.; Fujii, N. J. Org. Chem. 2000, 65, 4888–4899. (d) Behr, J. B.;
Evina, C.; Phung, N.; Guillerm, G. J. Chem. Soc., Perkin Trans. 1 1997,
1597–1599. (e) Cox, R. J.; Gibson, J. S.; Mayo-Martin, M. B. ChemBioChem
2002, 3, 874–886. (f) Han, S.; Moore, R. A.; Viola, R. E. Synlett 2003, 6, 845–
846. For examples on synthesis of R-fluoro-β-aminophosphonates, see: (g)
Roschenthaler, G. V.; Kukhar, V.; Barten, J.; Gvozdovska, N.; Belik, M.;
Sorochinsky, A. Tetrahedron Lett. 2004, 45, 6665–6667. (h) Roschenthaler,
G. V.; Kukhar, V.; Belik, M.; Mazurenko, K. I.; Sorochinsky, A. Tetrahe-
dron 2006, 62, 9902–9910. (i) Zheng, W. H.; Yuan, Ch. Y. Chin. J. Chem.
2006, 24, 1170–1174. (j) Henri-dit-Quesnel, A.; Toupet, L.; Pommelet, J. C.;
Lequeux, T. Org. Biomol. Chem. 2006, 4, 2486–2491.
(13) Palacios, F.; Acparicio, D.; Ochoa de Retana, Ac. M.; de los Santos,
J. M.; Gil, J. I.; Lopez de Munain, R. Tetrahedron: Asymmetry 2003, 14,
689–700.
(14) (a) Palacios, F.; Aparicio, D.; de los Santos, J. M.; Rodriguez, E.
Tetrahedron 1998, 54, 599–614. (b) Palacios, F.; Aparicio, D.; Garcia, J.
Tetrahedron 1996, 52, 9609–9628.
(15) Zapata, A. J.; Gu, Y.; Hammond, G. B. J. Org. Chem. 2000, 65, 227–
234.
1172 J. Org. Chem. Vol. 76, No. 4, 2011

Radwan-Olszewska et al.
JOCNote
Experimental Section
(CDCl3) δH 1.31-1.39 (m, 6H), 2.36 (s, 3H), 4.19-4.25(m, 4H),
5.13 (dd, 1H, 2JHF = 47.30 Hz, 2JHP = 14.32 Hz); 13C NMR
General Procedure for Selective Fluorination of β-Ketophos-
phonates by Selectfluor. To a stirred solution of appropriate
β-ketophosphonate 1 (1.0 mmol) in dry acetonitrile (20 mL)
at room temperature was added Selectfluor (2.0 mmol, 0.71 g for
monofluorination or 6.0 mmol, 2.1 g to obtain difluorinated
product), and stirring was continued for 10 min. After that
reaction time, the vessel was heated to reflux, and the heating
was continued for 24 h. Next, the reaction mixture was cooled
to room temperature, and Et2O (30 mL) was added followed
by addition of saturated aqueous NH4Cl (20 mL). The layers
were separated, and the organic layer was washed with brine
(2 ꢀ 15 mL) and H2O (1 ꢀ 15 mL), dried over anhyd MgSO4,
and concentrated under reduced pressure affording the crude
product that was further purified by column chromatography
(SiO2, EOAc/hexane).
(CDCl3) δC 16.3, 26.7, 64.1, 91.6 (dd, JCP = 152.61 Hz, JCF
=
197.54 Hz), 200.7 (d, JCF = 20.37 Hz); 31P NMR (CDCl3) δP
2
10.1 (d, JPF = 71.47 Hz); FTIR (neat) νmax (cm-1) 1734
(CdO), 1258 (PdO); CIMS m/z 212 ([Mþ], 25); HRMS calcd
for C7H15FO4P (M þ H)þ 213.0614, found 213.0615.
Acknowledgment. Polish State Committee for Scientific
Research (K.B.N.) is acknowledged for financial support
(Grant No. 1297/T09/2005/29). K.R.-O. is grateful to Wroc-
law University of Technology and University of the Basque
Country for predoctoral scholarship.
Supporting Information Available: Detailed experimental
P
procedures, full characterization, and copies of 1H, 13C, and 31
Diethyl 1-fluoro-2-oxopropylphosphonate (2b): colorless oil
(131 mg, 62%); Rf = 0.40 (EtOAc/pentane 2:1); 1H NMR
NMR spectra for compounds 2-5 and 7. This material is
available free of charge via the Internet at http://pubs.acs.org
J. Org. Chem. Vol. 76, No. 4, 2011 1173