Given the continued and recent interest in this pyrophos-
phate mimic, we wish to provide an improved and robust
method for its preparation.
inexpensive. With the added convenience of a single step,
we decided to choose this method for improvement.
In our initial study, tetraisopropyl methylenediphospho-
nate, 3a, was treated with 2.0-3.3 equiv of base (e.g.,
KHMDS, NaHMDS, LiHMDS, NaH, KH) followed by
9
Generally, the synthesis of 2 requires construction of
tetraalkyl difluoromethylenediphosphonate, 1, followed by
deprotection of the phosphate ester groups (Scheme 1).
2.0-3.6 equiv of NFSi (Scheme 3). Crude reaction mixtures
A standard method for the preparation of 1 is not apparent
in the literature, but it has been accomplished using a variety
1
0
of innovative chemistries over the last 25 years. We set
out to improve the synthesis of 1 in order to provide a
scalable, robust, high-yielding route to compound 2 using
readily available chemicals and minimal synthetic steps.
Scheme 3
A general route for the construction of 1 is the reaction
between phosphonate carbanions (derived from methylene
diphosphonate, 3, and a strong base) and electrophilic
fluorinating reagents which provide a source of electrophilic
were analyzed by 31P NMR for the presence of product 1c,
10
+
starting material 3a, partial product fluoromethylenediphos-
phonate, 4, and unidentified impurities. In all cases, varied,
but persistent, amounts of unreacted 3a and 4 were observed
in the reaction mixtures. Furthermore, compound 4 has an
fluoride (F ) (Scheme 2).
Scheme 2
f
R similar to that of the desired product, and as a result,
efficient removal of this impurity by flash chromatography,
particularly on a multigram scale, was not trivial.
With similar results from different bases, it was apparent
that the choice of base was not a critical factor for minimizing
undesired 3a or 4; therefore, we chose to continue our study
with the convenient NaHMDS solution.
Because NaHMDS is a strong base, reactions using this
reagent are typically performed at -78 °C to allow more
control of the reaction and to minimize the formation of side
products. However, since diphosphonate 3a is relatively
stable, we decided to explore higher reaction temperatures,
while maintaining the equivalents of NaHMDS and NFSi at
The synthesis of 1 using NFSi was first reported by Gosse-
11
12
lin (>34% yield). Blackburn (50% yield) and Lebeau
8c
(
68-78% yield) have also reported this method. Tetraalkyl
methylenediphosphonates and other reagents used in this
route are readily available commercially and are relatively
(4) For example: (a) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J.
3
and 3.3, respectively. Encouragingly, the ratio of 1c to 3a
Chem. Soc., Chem. Commun. 1981, 22, 1188-1190. (b) Blackburn, G. M.;
and 4 improved with increased temperature (-20 °C, 0 °C,
25 °C, and reflux), but compounds 3a and 4 still remained.
Kent, D. E.; Kolkmann, F. J. Chem. Soc., Perkin Trans. 1 1984, 5, 1119-
1
125. (c) Blackburn, G. M.; Perree, T. D.; Rashid, A.; Bisbal, C.; Lebleu,
B. Chem. Scr. 1986, 26 (1), 21-24.
5) For example: (a) Davisson, V. J.; Woodside, A. B.; Neal, T. R.;
Stremler, K. E.; Muehlbacher, M.; Poulter, C. D. J. Org. Chem. 1986, 51
25), 4768-4779. (b) Stremler, K. E. and Poulter, C. D. J. Am. Chem. Soc.
987, 109 (18), 5542-5544.
6) For example: (a) Davisson, V. J.; Davis, D. R.; Dixit, V. M.; Poulter,
31
Significantly, no additional impurities were observed by P
(
NMR under these conditions, therefore it was evident that
cooling the reaction mixture was not necessary.
We then experimented with incremental, alternate addi-
tions of NaHMDS and NFSi without cooling the reaction
mixture. Thus, 3a was treated with 3.3 equiv of NaHMDS
(
1
(
C. D. J. Org. Chem. 1987, 52, 2 (9), 1794-1801. (b) Ariza, M. E.; Leeds,
J. M.; Williams, M. V.; Boyle, N. A.; Wang, G.; Prhavc, M.; Rajwanshi,
V.; Chen, F.; Brooks, J.; Hurd, T.; Cook, P. D. Poster presentation at the
4
(
3rd Interscience Conference on Antimicrobial Agents and Chemotherapy
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(
5
3
(
(
2
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