A new route to α-alkyl-α-fluoromethylenebisphosphonates

Article abstract of DOI:10.1039/c1ob05095h

A new route to α-alkyl-α-fluoromethylenebisphosphonates, 2 has been developed starting from commercially available tetraethyl fluoromethylenebisphosphonate (1), and alkyl halides using either caesium carbonate in DMF or sodium dimsyl. De-esterification of 2 provided biologically important α-alkyl-α-fluoromethylenebisphosphonic acid, 3, while alkoxide-induced carbon-phosphorus bond cleavage of 2 gave α- fluorophosphonates, 4, which are useful synthons in organic synthesis.

Full text of DOI:10.1039/c1ob05095h

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A new route to a-alkyl-a-fluoromethylenebisphosphonates†
Petr Beier,*a Stanislav Opekar,a Mikhail Zibinsky,b Inessa Bychinskayab and G. K. Surya Prakash*b
Received 18th January 2011, Accepted 10th March 2011
DOI: 10.1039/c1ob05095h
A new route to a-alkyl-a-fluoromethylenebisphosphonates,
2 has been developed starting from commercially avail-
able tetraethyl fluoromethylenebisphosphonate (1), and alkyl
halides using either caesium carbonate in DMF or sodium
dimsyl. De-esterification of 2 provided biologically impor-
tant a-alkyl-a-fluoromethylenebisphosphonic acid, 3, while
alkoxide–induced carbon–phosphorus bond cleavage of 2
gave a-fluorophosphonates, 4, which are useful synthons in
organic synthesis.
as trimethylsilyl,11 arylsulfonyl12 or a second phosphonate group
(i.e. using bisphosphonates).13 These modifications significantly
prolong the nucleophile lifetime and prevent a-eliminations.
Bisphosphonates are compounds of interesting biological prop-
erties and currently there are a number of approved pharmaceu-
ticals used for the treatment of various bone diseases (Fig. 1).
These drugs are non-hydrolysable analogues of the endogenous
pyrophosphate in which the oxygen bridge is replaced by a carbon
atom bearing two groups. Usually one of these groups is an organic
chain that determines the mode of action and the drug’s activity.
The other group mainly affects pharmacokinetics and it is usually
a hydroxyl group.
Phosphonates are important non-hydrolyzable mimics of phos-
phates and are used in the synthesis of nucleotide analogs as
probes for various enzymes,1,2 in bone cancer treatments as carriers
of radioactive 153Sm,3 in inorganic chemistry as chelating agents,
etc.4 They also have found several industrial applications.5 The
replacement of the oxygen bridge of the biological phosphate
with the difluoromethylene or monofluoromethylene groups leads
to isosteric analogues having acid dissociation constants almost
identical with those of the natural phosphate.6 This concept,
introduced by Blackburn and co-workers,7 led to the synthesis
of a variety of biologically active fluorinated phosphonates and
their successful deployment in many areas of biological chemistry.1
Fluorinated phosphonates can be prepared in a number of
different ways depending on the nature of organyl moiety. One
of the common methods is their synthesis via fluorinated phos-
phonate carbanions. A central issue in nucleophilic displacement
chemistry involving a-fluorinated phosphonoalkyl anions is the
a-elimination of the phosphite or fluoride to produce carbenoid
species leading to decomposition and generally lower yields. In
case of difluorophosphonate metal species8 this problem has been
overcome by using either reactive electrophiles such as primary
alkyl triflates9 or by stabilization of the carbanion with cadmium or
zinc.10 The resulting reagents can be directly coupled with reactive
alkyl halides or even with aryl halides or alkynyl halides, in the
presence of Cu(I). Another way is to introduce a second anion-
stabilizing group in addition to the original phosphonate such
Fig. 1 Structures of bisphosphonate drugs currently used as anti-resorp-
tive agents.
The presence of the a-OH in bisphosphonates is believed
to enhance bone mineral binding compared to their hydrogen
derivatives.14 The bisphosphonate drugs work by inhibiting farne-
syl pyrophosphate synthetase (FPPS), one of the key enzymes
in the mevalonate pathway. From the crystal structure of the
risedronate–FPPS complex it was found that the a-OH group
does not chelate magnesium ions in the enzyme active site and
contributes indirectly to the phosphonate anion interaction with
Mg2+ by the electron-withdrawing effect of oxygen.15 In principle,
this effect should be exerted by other electron-withdrawing groups
such as fluorine. This substitution might lead to a new class of anti-
resorptive agents with better properties. Risedronate analogues
shown in Fig. 2 were reported to retain biological activity but
aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of
the Czech Republic, Flemingovo na´m. 2, 166 10, Prague 6, Czech Republic.
E-mail: beier@uochb.cas.cz; Fax: +420 233 331 733; Tel: +420 220 183 409
bLoker Hydrocarbon Research Institute, Department of Chemistry, Uni-
versity of Southern California, Los Angeles, CA, 90089-1661, USA.
E-mail: gprakash@usc.edu; Fax: +1 213 740 6270; Tel: +1 213 740 5984
† Electronic supplementary information (ESI) available: Experimental
procedures and full spectroscopic data for all new compounds. See DOI:
10.1039/c1ob05095h
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Table 1 Synthesis of 2 from 1 by alkylation
Entry
RX
Methoda
Time (h)
2, Yield (%)b
1
2
3
MeI
MeI
A
B
A
22
1
144
2a, 85
2a, 62
2b, 57
Fig. 2 Biologically active Risedronate analogues.
possess reduced bone affinity, which may be useful therapeutically
in certain situations.16
4
5
6
A
A
B
72
160
1
2c, 50
2c, 78
2c, 59
Direct installation of an alkyl, aryl or heteroaryl group on
CH–acidic bisphosphonate is problematic due to their rather low
acidity, significant steric hindrance resulting in lowered nucle-
ophilicity, and their tendency to undergo transesterification.16,17
Furthermore, as already mentioned, some of CH–acidic com-
pounds bearing fluorine atom undergo loss of fluoride ion upon
deprotonation.18 Due to these reasons, fluorobisphosphonate is
considered to be a challenging synthon for undergoing simple
alkylation protocols.1
7
A
96
2d, 57
8
A
A
A
A
B
85
19
120
20
12
2e, 22
2e, 74
2f, 82
2g, 0c
2h, 59
9
10
11
12
Previously,
a-alkyl-a-fluoromethylenebisphosphonates
2
have been prepared by an electrophilic fluorination
of a-alkylmethylenebisphosphonates accessible by either
alkylation of methylenebisphosphonate16a or reaction of
bis(diethylphosphono)ethylene
with
nucleophiles
such
13
14
15
A
B
B
20
1
2i, 74
2i, 83
2j, 43
as potassium imidazolide or aryllithium reagents.19 The
second route makes use of lithium salt of tetraethyl
fluoromethylenebisphosphonate (1) in reactions with methylating
reagents such as iodomethane or dimethylsulfate.13 The above
mentioned methods suffer either from unavailability of starting
compounds, low yields or long reaction sequences. Furthermore,
the lithium salt of 1 was reported to be unreactive towards other
alkylating reagents such as iodoethane.13a
2
16
17
B
B
2
1
2k, 45
2l, 50
We decided to develop a general methodology towards a-alkyl-
a-fluoromethylenebisphosphonates 2, which would start from
tetraethyl fluoromethylenebis-phosphonate (1) – a compound
commercially available or easily prepared by electrophilic fluo-
18
19
B
B
3
2m, 46
2n, 43
R
rination of tetraethyl methylenebisphosphonate with Selectfluorꢀ
in ca 50% yield.20 Taking into account principal possibility of
fluoride elimination and formation of carbene species screening of
various bases was performed in the reaction of 1 with two model
alkylating reagents: 1-iodoheptane and benzyl bromide. While the
use of DBU, i-PrNEt2, t-BuOK, NaHMDS, CsF or K2CO3 in
THF or DMF solvents was not met with success, excess of caesium
carbonate in DMF or sodium hydride in DMSO were identified
as optimal conditions.
12
a Method A: Cs2CO3 (2 eq), DMF, rt; Method B: NaH (1.1 eq), DMSO, 0
◦C to rt. b Isolated yield. c Styrene formed instead of 2g.
due to limited stability of the caesium salt of 1 under elevated
temperatures. For example, in the reaction with allyl bromide at
50 ◦C the yield of 2c was only 14% after 18 h and it did not increase
further under prolonged reaction times.
Satisfactory results have also been obtained using sodium
hydride in DMSO (Method B). Reactions proceeded faster under
these conditions, however they gave lower yields in some cases.
In case of using chloromethylthiirane as the alkylating reagent
(Table 1, entry 12), the formation of thietane substituted fluo-
robisphosphonate was not observed, which points to substitution
process close to SN2. It was thus shown that the caesium or sodium
salt of 1 could be formed using a suitable base, the salts do not
expel fluoride and are stable at ambient temperature in DMSO or
Various alkyl halides were used to determine the scope and
limitation of the reaction (Table 1). With excess of caesium
carbonate in DMF (Method A) primary alkyl iodides reacted
well, except for PhCH2CH2I which gave styrene by b-elimination
as the main product under the reaction conditions. Primary alkyl
bromides were also reactive, however, in some cases rather long
reaction times were needed to achieve good results. The reactivity
of primary alkyl chlorides was significantly reduced compared to
iodides and bromides. Finally, 2-iodopropane as an example of
a secondary alkyl iodide reacted reasonably well and provided
the product 2d in good yield (Table 1, entry 7). Reaction times
could not be shortened by increasing temperature presumably
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Table 2 Synthesis of 4 from 2 by the action of magnesium ethoxide
one-step reaction, which takes place at ambient temperature
and under mild reaction conditions. Straightforward de-
esterification of
2 provides important biologically active
a-alkyl-a-fluoromethylenebisphosphonic acids 3. Alkoxide–
induced carbon–phosphorus bond cleavage of 2 provides a new
way to a-fluorophosphonates 4.
Entry
2, R
Temp. (◦C)
Time (h)
4, Yield (%)a
Support of this work at the Institute of Organic Chemistry
by the Grant Agency of the Czech Republic (203/08/P310) and
the Academy of Sciences of the Czech Republic (Research Plan
AVZ40550506) is gratefully acknowledged. Work at the University
of Southern California (USA) was supported by the NIH grant,
5-U19-CA105010 and the Loker Hydrocarbon Research Institute.
1
2
2a, Me
145
90
22
18
4a, 26b
4c, 5c
2c,
CH2 CHCH2
2e, n-Bu
2f, n-C7H15
2i, Bn
3
4
5
150
155
100
20
44
20
4e, 61
4f, 62
4i, 50
a Isolated yield. b 4a was obtained as inseparable mixture with triethylphos-
phate. c Number of side products were formed.
Notes and references
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DMF and nucleophilic enough to undergo the desired alkylation
reactions unlike the lithium salt of 1.
De-esterification of selected phosphonates 2 using literature
conditions21 gave a-alkyl-a-fluoromethylenebisphosphonic acids,
3 in excellent yields (3a, R = Me, 97%; 3i, R = Bn, 92%). This two
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the synthesis of phosphonic acids 3.
A possibility of cleavage of one of the phosphoryl groups of
bisphosphonates 2 to a-fluorophosphonates 4 was also investi-
gated. This transformation would be analogous to the reduc-
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sodium amalgam or magnesium metal in the presence of protic
solvent.12,22 Alkoxide induced P–CF3 bond cleavage has been
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trifluoromethylphosphonate.23 It was expected that a nucleophile
such as alkoxide anion would attack one phosphorus atom of
2, followed by the cleavage of carbon–phosphorus bond to give
a-fluorophosphonates 4. Reaction of 2e with EtONa (20 eq)
in EtOH at ambient temperature gave only traces of expected
diethyl (1-fluoropentyl)phosphonate (4e) after 17 h. At 50 ◦C
under otherwise identical conditions the product conversions
were 55% after 5 h and 30% after 17 h with the formation of
many side products. Reaction of 2e with Mg (10 eq) in MeOH
at ambient temperature provided a mixture of methyl and ethyl
bisphosphonates after 1.5 h and a mixture of methyl and ethyl (1-
fluoropentyl)phosphonate after 17 h. Finally, it was decided to use
magnesium ethoxide in ethanol24 to avoid the formation of mixture
of products by transesterification and the results are summarized
in Table 2. It was found that excess (10 eq) of magnesium ethoxide
and elevated temperature are needed to achieve moderate to good
yields of fluorophosphonates 4. Careful temperature control plays
a crucial role. For example, with the benzyl derivative 2i, the
optimal temperature was found to be 100 ◦C. Below 90 ◦C the
reaction was very sluggish, while above 120 ◦C there was a number
of side-products formed. For alkyl derivatives 2a, 2e, 2f the optimal
temperature was 145–155 ◦C. This process represents novel and
interesting C–P bond cleavage of fluorinated bisphosphonates to
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a
new route to a-alkyl-a-fluoro-
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fluoromethylenebisphosphonate (1) and alkyl halides has
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