J . Org. Chem. 2001, 66, 327-329
327
Novel Syn th esis of
P ]-(2-Ch lor oeth yl)p h osp h on ic Acid
labeled phosphonic acid derivatives did not meet these
specifications.5
[33
Nanjing Zhang and J ohn E. Casida*
Environmental Chemistry and Toxicology Laboratory,
Department of Environmental Science, Policy and
Management, University of California,
Berkeley, California 94720-3112
We report here a novel and convenient route, starting
3
3
33
3 4
from [ P]-H PO , to synthesize [ P]-ethephon with high
yield and purity, which can also be applied to a variety
of phosphonic acids and their derivatives.
Received September 14, 2000
Phosphonic acids and their derivatives play an impor-
tant role in the regulation of biological processes. They
1
Resu lts a n d Discu ssion
are widely used as pharmaceuticals and agrochemicals,
e.g., glyphosate [N-(phosphonomethyl)glycine] as a her-
bicide and ethephon [(2-chloroethyl)phosphonic acid] as
There are two major approaches to form the phospho-
rus-carbon bond: (1) the attack of a phosphorus or
phosphoric acid derivative (a halide or an ester) by an
organometallic reagent and (2) the nucleophilic attack
by a trivalent phosphorus center on electrophilic car-
2
a plant growth regulator. Their safe and effective use
requires a thorough understanding of their metabolic fate
and toxicology. For example, ethephon inhibits plasma
butyrylcholinesterase in mammals including humans,
presumably by phosphorylation of a serine residue at the
1,6
bon. Direct synthesis of ethephon by the first approach
is not achievable due to the nonavailability of a â-chloro
organometallic reagent. Indirect synthesis, e.g., through
the sequence aldehyde, alcohol, and chloride, requires
several reaction and purification steps with only moder-
3
active site. Further study of the mechanism and conse-
quences of this enzyme inhibition and possible phospho-
rylation of other proteins required the radiosynthesis of
7
ate yield, which is not suitable for radiolabeling.
3
3
[
P]-ethephon.
Ethephon is normally synthesized by the second ap-
The challenge for radiosynthesis of ethephon lies in
8
proach through an Arbuzov reaction, either via coupling
formation of the phosphorus-carbon bond starting from
of a trialkyl phosphite with 1-bromo-2-chloroethane or
by intramolecular rearrangement of tris(2-chloroethyl)
phosphite. In both cases, the final step is acid hydrolysis
3
3
the most readily available precursor, [ P]-phosphoric
acid (H PO ). In addition, the acid nature of ethephon
3
4
as well as its instability under neutral and basic condi-
9
or reaction with trimethylsilyl bromide for dealkylation
4
tions require a clean and efficient procedure to minimize
of the resulting phosphonate to the phosphonic acid. We
examined the Arbuzov reaction of several trialkyl phos-
phites [trimethyl, triethyl, triisopropyl, and tris(2-chlo-
roethyl)] and found that, besides the long time (>16 h)
and high temperature (∼160 °C), the procedure gives a
series of byproducts presumably from attack at the
chloro-substituted carbon or intermolecular Arbuzov
reaction.10 Impurities in trialkyl phosphites from the
purification. Earlier multistep syntheses of 32P- and P-
33
*
To whom correspondence should be addressed. Tel: (510) 6425424.
Fax: (510) 6426497. E-mail: ectl@nature.berkeley.edu.
1) (a) Engel, R. The Use of Carbon-Phosphorus Analogue Com-
(
pounds in the Regulation of Biological Processes in Handbook of
Organophosphorus Chemistry; Engel, R. Ed.; Marcel Dekker Inc: New
York, 1992; pp 559-600. (b) Engel, R. Synthesis of Carbon-Phosphorus
Bonds; CRC Press Inc: Boca Raton, 1988.
(
2) Eto, M. Organophosphorus Pesticides: Organic and Biological
Chemistry; CRC Press: Cleveland, 1974.
3) (a) Hennighausen, G.; Tiefenbach, B.; Lohs, Kh. Pharmazie 1977,
3
reaction of phosphorus trichloride (PCl ) with alcohol
significantly increase the amounts of side products.
Difficulties are also reported in completely hydrolyzing
(
3
2, 181-182. (b) Hennighausen, G.; Tiefenbach, B. Arch. Exp. Veteri-
naermed. 1978, 32, 609-621. (c) Environmental Protection Agency.
Fed. Regist. 1997, 62, 2149-2154. (d) Haux, J . E.; Quistad, G. B.;
Casida, J . E. Chem. Res. Toxicol. 2000, 13, 646-651.
10b,11
to the desired phosphonic acids.
We therefore chose to use a more bulky and more
reactive phosphite, tris(trimethylsilyl) phosphite
(
4) (a) Maynard, J . A.; Swan, J . M. Aust. J . Chem. 1963, 596-608.
(
1
b) Gregory, M. J .; Higgins, G. M. C. J . Chem. Soc., Perkin Trans. 2
973, 711-713. (c) Segall, Y.; Toia, R. F.; Casida, J . E. Phosphorus,
Sulfur Silicon Relat. Elem. 1993, 75, 191-194.
5) For 32P-labeling of compounds with phosphorus-carbon bond-
s), see: (a) Murray, A., III; Williams, D. L. Phosphorus-32 Compounds
3
[P(OTMS) ], expecting that it would provide higher
selectivity between the carbons with bromide and chlo-
(
ride and also a milder reaction condition. This proved to
(
12
be the case, and the Arbuzov reaction of P(OTMS)
3
with
in Organic Syntheses with Isotopes; Interscience Publishers Inc: New
York, 1958; pp 1899-1928. (b) Reesor, J . B.; Perry, B. J .; Sherlock, E.
Can. J . Chem. 1960, 38, 1416-1427. (c) Schuette, H. R. Org. Soedin.,
Mechennye Radioakt. Izot., Mater. Simp. Stran-Chlenov SEV, 2nd;
TsNIIatominform: Moscow, USSR, 1981 (pub. 1982), 1, 253-9. Chem.
Abstr. 1984, 101, 145851s. (d) Fortineau, A.-D.; Brichory, F.; Pellen,
P.; Sai, C.; Dazord, L.; Mortier, J .; Vaultier, M.; Bourguet, P. J . Labeled
Compd. Radiopharm. 1999, 42, 527-536.
1
-bromo-2-chloroethane in 1,2-dichloroethane was almost
complete on refluxing for 2 h, giving the desired com-
pound exclusively, but the reaction with 1,2-dichloro-
(9) (a) McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M.-
C. Tetrahedron Lett. 1977, 155-158. (b) McKenna, C. E.; Schmidhaus-
er, J . J . Chem. Soc., Chem. Commun. 1979, 739.
(6) For reactions of phosphate with organometallic reagents, see:
(
a) Teulade, M.-P.; Savignac, P. Tetrahedron Lett. 1987, 28, 405-408.
(10) For possible routes to form byproducts, see: (a) Segall, Y.;
Grendell, R. L.; Toia, R. F.; Casida, J . E. J . Agric. Food Chem. 1991,
39, 380-385. (b) Cauret, L.; Brosse, J .-C.; Derouet, D.; De Livonni e` re,
H. Bull. Soc. Chim. Fr. 1997, 134, 463-470.
(b) Savignac, P.; Teulade, M.-P.; Patois, C. Phosphorus, Sulfur Silicon
Relat. Elem. 1990, 49, 169-172. (c) Patois, C.; Savignac, P. Bull. Soc.
Chim. Fr. 1993, 130, 630-635. (d) Dalpozzo, R.; De Nino, A.; Miele,
D.; Tagarelli, A.; Bartoli, G. Eur. J . Org. Chem. 1999, 2299-2301.
(11) Cauret, L.; Brosse, J . C.; Derouet, D.; De Livonni e` re, H. Synth.
Commun. 1997, 27, 647-653.
(
7) Zhang, N.; Casida, J . E. Unpublished results.
8) For a review on the Arbuzov reaction, see: Bhattacharya, A. K.;
(
(12) Rosenthal, A. F.; Vargas, L. A.; Isaacson, Y. A.; Bittman, R.
Tetrahedron Lett. 1975, 977-980.
Thyagarajan, G. Chem. Rev. 1981, 81, 415-430.
1
0.1021/jo0013608 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/02/2000