TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8711–8712
Reactions of diethyl mesyl- or tosyloxyphosphonates with diethyl
phosphite and base: a method claimed to yield bisphosphonates
,
Erik Arstad and Lars Skattebøl*
Department of Chemistry, University of Oslo, POB 1033 Blindern, 0315 Oslo, Norway
Received 20 August 2002; revised 20 September 2002; accepted 26 September 2002
Abstract—Reactions of diethyl mesyl- or tosyloxyphosphonates with sodium diethyl phosphite in THF lead to the corresponding
phosphono phosphates. Reaction of the mesyloxy derivative with diethyl phosphite in pyridine gives the phosphono phosphate as
minor product. Neither method yields bisphosphonates. © 2002 Elsevier Science Ltd. All rights reserved.
In connection with a study1 having as its goal the
introduction of radioactive iodine into bone struc-
tures, one target molecule was tetraethyl m-iodoben-
phosphite in THF afforded the phosphono phosphate
2b6 in 73% yield; by using the tosylate 3c under the
same reaction conditions the yield of 2b was
improved to 89%. Moreover, a similar reaction of the
tosylate 4b afforded the phosphono phosphate 2a in
63% yield. No detectable amounts of the bisphospho-
nates 1b and 1c, respectively, were formed under
these reaction conditions. The structure of compound
2b was established by comparison of the spectral data
with those of an authentic sample, prepared from 3a
and diethyl chlorophosphate.7
zylidenebisphosphonate
1a.
3-Nitrobenzaldehyde
seemed a convenient starting material, particularly
since Li and Yuan2 have published what appeared to
be a simple one-pot synthesis of tetraethyl bisphos-
phonates from aldehydes. The method involves con-
densation of diethyl phosphite with an aldehyde in
pyridine solution to the corresponding hydrox-
yalkylphosphonate that without isolation, is trans-
formed into the mesylate. Further reaction in the
same pot with diethyl phosphite was reported to give
excellent yields of bisphosphonates. However, subject-
ing 3-nitrobenzaldehyde to this protocol resulted in a
complex product mixture, in which no detectable
amount of the bisphosphonate 1b was present. Start-
ing from benzaldehyde we then attempted the synthe-
sis of tetraethyl benzylidenebisphosphonate 1c as
described by Li and Yuan. The crude product con-
sisted of a complex mixture of compounds, containing
the phosphono phosphate 2a3 as a minor constituent,
but none of the bisphosphonate 1c as claimed. An
authentic sample of the latter was prepared from
diethyl benzylphosphonate according to the literature4
and the physical and spectroscopic data differ signifi-
cantly from those reported by Li and Yuan.2
Creary and co-workers8 have reported that solvolysis
of the mesylate 4a gave exclusively substitution prod-
ucts, derived from an intermediate carbocation. Our
results appear anomalous, but the conditions should
favour an SN2 reaction, which is disfavoured by both
a crowded benzylic carbon and a bulky nucleophile.
Hence, another reaction path may become competi-
tive, and we suggest the intermediate formation of the
ketone 5.9 It is known to give a high yield of the
phosphono phosphate 2a with diethyl phosphite in
the presence of a base,10 a reaction involving the
facile rearrangement of an initially formed hydroxy-
bisphosphonate anion.7 The ketone 5 may result from
abstraction of the benzylic proton of the sulfonate
esters, facilitated by the neighbouring diethylphospho-
nate group, followed by elimination of the sulfinate
anion. Support for such an oxidation process comes
from the work of Creary11 who showed that similar
reactions on triflates lead to ketones. Furthermore,
when we treated the tosylate 4b with sodium ethoxide
in ethanol, one of the products was ethyl benzoate,
indicating the intermediacy of the ketone 5.9
On the other hand, the reaction of 3-nitrobenzalde-
hyde with diethyl phosphite using potassium fluoride
as base and no solvent5 furnished the hydroxyphos-
phonate 3a6 in almost quantitative yield. Treatment
of the corresponding mesylate 3b with sodium diethyl
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02143-3
?rstad, Erik
