A general procedure for the preparation of β-ketophosphonates

Article abstract of DOI:10.1021/jo901552k

(Chemical Equation Presented) A mild, high-yielding procedure for the preparation of β-ketophosphonates is described. The condensation is general with respect to the ester and phosphonate, and the products are obtained in high yields within minutes at 0°C. The reaction procedure is operationally simple and amenable to large-scale preparations. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901552k

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SCHEME 1. Condensation of LiCH2PO(OMe)2 with Esters
A General Procedure for the Preparation of
β-Ketophosphonates
Kevin M. Maloney* and John Y. L. Chung
Department of Process Research, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New Jersey 07065
kevin_maloney@merck.com
Received July 17, 2009
tonation of 1 with n-BuLi,4 LDA,5 or LiHMDS6 at -78 °C
followed by the addition of an ester as shown in Scheme 1. As
expected, a second equivalent of phosphonate anion (2) or
base is required to deprotonate the more acidic β-ketopho-
sphonate product (4). Though the reaction has been used on
several occasions for the large-scale synthesis of β-ketopho-
sphonates,7 the cryogenic conditions (-78 °C) and the
tendency of 2 to dimerize8 (2 f 7) or undergo an intermo-
lecular alkyl transfer9 (2 f 5þ6) severely limits this synthe-
tic route for large-scale preparations (Scheme 1). During the
preparation of this manuscript, a report was published by
Milburn and co-workers at Amgen detailing the develop-
ment of a mild preparation of aryl β-ketophosphonates.10
While this reaction procedure is an improvement over pre-
vious methodologies, the reaction conditions could not be
extended to aliphatic esters and esters with active R-protons.
In this Note, we wish to report the development of a general,
mild, high-yielding procedure for the preparation of β-keto-
phosphonates.
The key to the preparation of β-ketophosphonates under
noncryogenic conditions is the elimination of side reactions
associated with phosphonate anion 2 (Scheme 1). We envi-
sioned that generating anion 2 in the presence of ester 3
would lead to the instantaneous formation of β-ketopho-
sphonate 4 and the elimination of side reactions. In order to
test this hypothesis, we began with the synthesis of β-keto-
phosphonate 9. We discovered that simply adding a solution
of LDA to a mixture of 1 and 8 at 0 °C afforded 9 in 90%
yield. Only 1 equiv of phosphonate 1 was needed for com-
plete conversion, indicating that the decomposition of 2 was
completely suppressed. Attempts to use other bases includ-
ing n-BuLi and LiHMDS were complicated by competing
side reactions such as the Claisen condensation of 8.
A mild, high-yielding procedure for the preparation of
β-ketophosphonates is described. The condensation is
general with respect to the ester and phosphonate, and
the products are obtained in high yields within minutes at
0 °C. The reaction procedure is operationally simple and
amenable to large-scale preparations.
β-Ketophosphonates are versatile intermediates for the
synthesis of R,β-unsaturated carbonyl compounds via the
Horner-Wadsworth-Emmons (HWEs) reaction1 and for
liquid-liquid extraction of metal ions.2 Consequently, the
development of a reliable and scalable method for the
synthesis of β-ketophosphonates has been actively pursued
by several laboratories.3 Several methods exist for the pre-
paration of β-ketophosphonates, and the most common
method involves the condensation of methyl dialkylpho-
sphonates with esters. The condensation of dimethyl methyl-
phosphonate (1) with esters typically involves the depro-
(1) (a) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961,
83, 1733–1738. (b) Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87–99.
(c) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927. (d) Kelly, S.
E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 1, pp 729-818 and references therein.
(2) (a) Cotton, F. A.; Schunn, R. A. J. Am. Chem. Soc. 1963, 85, 2394–
2402. (b) Sturtz, G.; Clement, J. C.; Daniel, A.; Molinier, J.; Lenzi, M. Bull.
Soc. Chim. Fr. 1981, 167–171. (c) McCabe, D. J.; Duesler, E. N.; Paine, R. T.
Inorg. Chem. 1985, 24, 4626–4629.
Having identified mild conditions for the preparation of
β-ketophosphonate 9, the scope and generality of the pro-
cedure was examined. As shown in Table 1, the condensation
of several electronically and structurally diverse esters with
(3) (a) Arbuzov, B. A. Pure Appl. Chem. 1964, 9, 307–353. (b) Corey, E. J.;
Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654–5656. (c) Corbel, B.;
L’Hostis-Kervella, I.; Haelters, J.-P. Synth. Commun. 1996, 26, 2561–2568.
(d) Kim, D. Y.; Kong, M. S.; Kim, T. H. Synth. Commun. 1999, 29, 1271–
1274. (e) Du-Pisani, C.; Schneider, D. F.; Venter, P. C. R. Synth. Commun.
2002, 32, 305–314.
(4) For a recent example, see: Somu, R. V.; Boshoff, J.; Quao, C.;
Bennett, E. M.; Barry, C. E.; Aldrich, C. C. J. Med. Chem. 2006, 49, 31–34.
(5) For a recent example, see: Palacios, F.; Ochoa de Retanam, A. M.;
Alonso, J. M. J. Org. Chem. 2006, 71, 6141–6148.
(7) For the preparation of a ketophosphonate on 20 kg scale, see: Zhi-
Jiang Hisun Pharmaceutical Co. Ltd. The process and intermediates for the
selective synthesis of fluvastatin. WO Patent 2006021326, 2006.
(8) Tuelade, M.-P.; Savignac, P.; Aboujaoude, E. E.; Collignon, N.
J. Organomet. Chem. 1986, 312, 283.
(9) Yasuda, N.; Hsiao, Y.; Jensen, M. S.; Rivera, N. R.; Yang, C.; Wells,
K. M.; Yau, J.; Palucki, M.; Tan, L.; Dormer, P. G.; Volante, R. P.; Hughes,
D. L.; Reider, P. J. J. Org. Chem. 2004, 69, 1959–1966.
(6) For a recent example, see: Westermann, J.; Schneider, M.; Platzek, J.;
Petrov, O. Org. Proc. Res. Dev. 2007, 11, 200–205.
(10) Milburn, R. R.; McRae, K.; Chan, J.; Tedrow, J.; Larsen, R.; Faul,
M. Tetrahedron Lett. 2009, 50, 870–872.
7574 J. Org. Chem. 2009, 74, 7574–7576
Published on Web 09/03/2009
DOI: 10.1021/jo901552k
r
2009 American Chemical Society

Maloney and Chung
JOCNote
TABLE 1. LDA-Mediated Condensation of Various Esters with Phosphonate 1
aIsolated yields.
SCHEME 2. LDA-Mediated Condensation of MePO(OMe)2
with Ester 8
TABLE 2. LDA-Mediated Condensation of Various Phosphonates with
Ester 8
phosphonate 1 afforded the desired β-ketophosphonates in
excellent yield. The reaction procedure worked well with
esters having active R-protons as shown in entries 3 and 4. It
is noteworthy that substrate 16 having an acidic BocN-H
proton is tolerated under the reaction conditions by using an
extra equivalent of LDA (total of 3 equiv). Interestingly, we
discovered that the Weinreb amide derivative 16B afforded
17 in higher yield than the corresponding methyl ester
derivative 16A (92% versus 77%). Unfortunately, this was
not a general trend as methyl esters tend to give higher yields
than the corresponding Weinreb derivatives. In general, the
condensations were instantaneous at 0 °C and the β-ketopho-
sphonates were typically isolated in high purities (>90%) after
a simple aqueous workup. Also, we found that commercial
LDA solutions11 worked as well as prepared LDA solutions
further simplifying the procedure.
aUsed 1.1 equiv of phosphonate. bIsolated yields.
Next, we set out to explore the reactivity of different
phosphonates with ester 8 using our standard procedure
(11) 2.0 M solution of LDA purchased from Sigma Aldrich.
J. Org. Chem. Vol. 74, No. 19, 2009 7575

Maloney and Chung
JOCNote
(Table 2). As shown in entries 1 and 2, R-substitued phos-
phonates 26 and 28 afforded the desired β-ketophosphonates
27 and 29 in 97% and 85% yield, respectively. In addition,
phosphonate 30 reacted with ester 8 under our standard
conditions to give 31 in 90% yield. This clearly demonstrates
that steric differences in the phosphonate have little influence
on the yield and rate of the condensation reaction. Unfortu-
nately, we were unable to extend the reaction conditions to
the preparation of trifluoroethyl-substituted β-ketophosh-
ponates such as 33, which are key reagents for the
Still-Gennari-modified HWE reaction12 (entry 4). Presum-
ably, the electron-withdrawing trifluoroethyl groups make
the dimerization of 32 more favorable than the competing
condensation reaction (see Scheme 1).
In conclusion, we have developed a mild, noncryogenic
procedure for the synthesis of β-ketophosphonates. The con-
densation is general with respect to the ester and phosphonate
and the products are obtained in high yields within minutes at
0 °C. The mild conditions and the operational simplicityof the
procedure make it amenable to large-scale applications. In
addition, the condensation works with commercial LDA
solutions further simplifying the procedure.
round-bottomed flask equipped with a nitrogen inlet adap-
ter, addition funnel, thermocouple, and mechanical stirrer
was charged with ester 8 (20 g, 122 mmol), dimethyl methyl-
phosphonate 1 (14.5 mL, 16.6 g, 134 mmol), and 200 mL
of THF. The reaction mixture was cooled at -5 °C while a
2.0 M solution of LDA (128 mL, 256 mmol) was added
dropwise via addition funnel keeping the internal tempera-
ture below 0 °C. After complete addition, the reaction
mixture was stirred at 0 °C until complete consumption of
8 as determined by HPLC analysis (typically <5 min). The
reaction mixture was then carefully quenched with 5 M HCl
to adjust the pH to ca. 4 and diluted with EtOAc. The
aqueous layer was separated and extracted with EtOAc.
The combined organic layers were washed with water and
brine, dried over MgSO4, filtered, and concentrated to yield
32.0 g of β-ketophosphonate 9 (ca. 90% pure as judged
by HPLC and NMR analysis). Purification by column
chromatography afforded 28.1 g (90% yield) of 9 as a pale
yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.23-7.27 (m,
2 H), 7.14-7.18 (m, 3H), 3.72 (d, J = 11.2 Hz, 6 H), 3.05 (d,
J = 22.7 Hz, 2 H), 2.86-2.95 (m, 4 H); 13C NMR (100 MHz,
CDCl3) δ 200.9 (d, JCP = 6.3 Hz), 140.6, 128.5, 128.4, 126.1,
53.0 (d, JCP = 6.5 Hz), 45.5, 41.4 (d, JCP = 128.1 Hz), 29.4;
HRMS (m/z) [M þ H]þ calcd for C12H18O4P, 257.0943;
found, 257.0946.
Experimental Section
Representative Procedure. Preparation of (2-Oxo-4-phenyl-
butyl)-phosphonic Acid Dimethyl Ester (9). A 1-L, three-necked,
Supporting Information Available: Detailed experimental
procedures, characterization data, and copies of 1H and 13C
NMR spectra for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
7576 J. Org. Chem. Vol. 74, No. 19, 2009