A practical preparation of aryl β-ketophosphonates

Article abstract of DOI:10.1016/j.tetlet.2008.11.112

The condensation of alkyl phosphonates with aryl esters to give β-ketophosphonates may be carried out at elevated temperatures mediated by LiHMDS under Barbier type conditions. The reaction is scalable, does not require specialized cryogenic equipment, and is general for all aryl and heteroaryl esters examined.

Full text of DOI:10.1016/j.tetlet.2008.11.112

Tetrahedron Letters 50 (2009) 870–872
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical preparation of aryl b-ketophosphonates
*
Robert R. Milburn , Ken McRae, Johann Chan, Jason Tedrow, Robert Larsen, Margaret Faul
Small Molecule Process Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The condensation of alkyl phosphonates with aryl esters to give b-ketophosphonates may be carried out
at elevated temperatures mediated by LiHMDS under Barbier type conditions. The reaction is scalable,
does not require specialized cryogenic equipment, and is general for all aryl and heteroaryl esters
examined.
Received 29 October 2008
Revised 25 November 2008
Accepted 26 November 2008
Available online 3 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Ketophosphonates are extremely valuable synthetic intermedi-
ates owing to their application in the Horner–Wadsworth–Em-
mons (HWEs) reaction.1 Some notable features of the HWE
reaction that make it both general and scalable include the inex-
pensive and widespread availability of methyl dialkylphospho-
nates, the mild reaction conditions, and byproducts (phosphate
salts) that are benign, water soluble and therefore easily removed.
In addition, the esters used to make the ketophosphonates are typ-
ically stable and readily accessible. Although the condensation of
methyl dialkylphosphonates with esters has been used on a num-
ber of occasions for the large-scale preparation of ketophospho-
nates,2 the very low temperatures required (e.g., À78 °C), and the
tendency of methyl dimethylphosphonate to undergo an intermo-
lecular alkyl transfer can be a significant barrier to carrying out
these reactions on large scale.3,4
Condensation reactions of esters and methyl dialkylphospho-
nates to form ketophosphonates are typically carried out via
deprotonation of methyl dialkylphosphates with one equivalent of
n-BuLi,5 LDA,6 or LiHMDS7,8 at À78 °C followed by treatment of
the resulting anion with either esters and anhydrides or acid chlo-
rides. As with the Claisen condensation, a second equivalent of
base/alkylphosphonate anion is required to deprotonate the acidic
ketophosphonate product. For the large-scale synthesis of a HWE
adduct, a non-cryogenic aryl ketophosphonate synthesis was de-
sired. Based on a patent by Harada et al.9 which demonstrated the
use of LiHMDS for the condensation of methyl dimethylphospho-
nate with aromatic anhydrides at À20 °C, we attempted the reaction
of aryl esters with methyl dimethylphosphonate mediated by
LiHMDS, and found that this reaction could also be carried out at
elevated temperatures in very high yield (Table 1, entry 1).10 Further
study of the reaction showed that steric hindrance in the dialkyl
portion of the MePO(OR)2 or the alkyl portion of the aryl ester has
little influence on the yield of ketophosphonate, as dialkylphospho-
nates (Table 1, alkyl = methyl, ethyl, and isopropyl) along with iso-
propyl arylesters are uniformly compatible with the reaction.
However, diphenyl methyl- (entry 4) and bis(trifluoroethyl) meth-
ylphosphonates (entry 5), which would give access to valuable sub-
strates for the Still-Gennari-modified HWE reaction,11 are not
tolerated under these reaction conditions.12
The reaction is remarkably general for aryl esters (Table 2), and
tolerates both steric and electronic deactivation of the ester with-
out significant loss in yield. For extremely deactivated esters (entry
9), the reaction rate is significantly reduced, and these substrates
tend to give incomplete conversion under standard conditions
due to reagent (MePO(OMe)2/LiHMDS) decomposition. These reac-
tions can, however, proceed to completion using either additional
reagent (entry 9) or portionwise addition of reagent. Both
cient (entries 12 and 13) and -excessive (entries 10 and 11) het-
eroaryl esters participate in the reaction, giving clean 1,2-addition
products. Aliphatic esters and esters with active -protons are
p-defi-
p
a
incompatible with the reaction conditions and instead undergo
Claisen condensations.
Table 1
LiHMDS-mediated condensation of MePO(OR)2 with alkyl benzoates
O
O
O
P
OR2
OR2
O
P
LiHMDS
OR2
OR2
+
Ar
OR1
Ar
THF, 0 °C
Me
Entry
Ar
R1
R2
Product
Isolated yield, % (HPLC yield, %)
1
2
3
4
Ph
Me
Me
Et
iPr
Ph
1a
1b
1c
1d
92 (96)
91 (99)
91 (95)
—
5
5
6
7
Ph
iPr
CH2CF3
Me
Et
1e
2a
2b
2c
—
87 (99)
93 (99)
91 (95)
* Corresponding author.
E-mail address: rmilburn@amgen.com (R.R. Milburn).
iPr
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.112

R. R. Milburn et al. / Tetrahedron Letters 50 (2009) 870–872
871
Table 2
LiHMDS-mediated condensation of MePO(OMe)2 with aryl esters
O
O
O
P
ArCO2Me
LiHMDS
OMe
OMe
OMe
OMe
P
Me
Ar
O
O
P
O
O
P
LiHMDS
OMe
OMe
+
OMe
OMe
120
THF, 0 °C
Ar
OMe
Me
Ar
100
80
60
40
20
0
Entry
Ar
Ph
2-MeC6H4
4-MeC6H4
2-IC6H4
Product
Isolated yield, % (HPLC yield, %)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
2
3
4
5
6
7
8
9
10
11
12
13
92 (96)
95 (99)
94 (99)
80 (99)
99 (99)a
78 (99)
92 (99)
97 (98)
72 (—)b
66 (94)
91 (99)
99 (—)a
84 (92)
4-IC6H4
0
100
200
300
Time (min)
400
500
600
2-CF3C6H4
4-CF3C6H4
2-OMeC6H4
2,6-OMeC6H3
2-Furan
2-Thiophene
Nicoinate
5-Br 2-methoxy nicotinate
Figure 2. Decomposition of MePO(OMe)2/LiHMDS mixture at 0 °C.
slowly (t1/2 = 8 h) at 0 °C. Similar to observations using LDA,3 the
addition order in the preparation of the reagent is important, pre-
sumably due to reaction of the LiCH2PO(OMe)2 with the excess of
free MePO(OMe)2.
LiHMDS required to give complete conversion.
a
Isolated as Li salts.
b
2 equiv MePO(OMe)2 and 4 equiv.
In summary, we have found that MePO(OR)2/LiHMDS mixtures
have unusual stability at elevated temperatures, allowing for their
reaction with aromatic esters without the need for cryogenics.
Methyl dialkylphosphonates in general are compatible with these
conditions, but the diaryl- and di(trifluoroethyl)-phosphonates
used in Still-Gennari-modified HWE reactions11 are not accessible
using this methodology. The background decomposition of this
mixture is sufficiently slow at 0 °C (t1/2 = 8 h) to allow for complete
reaction of most aryl esters, but for less reactive systems where re-
agent decomposition competes with the desired condensation
reaction, incomplete conversions may be overcome by using addi-
tional reagent. In many cases, the lithio-ketophosphonates may be
isolated directly to give stable, non-hygroscopic salts, which have
been successfully used directly in subsequent HWE reactions with
aldehydes.
Although the aryl ketophosphonates are usually oils, their lithio
salts are typically non-hygroscopic and bench-stable solids, which
provide an effective control point and allow for purity upgrade
through recrystallization. In some cases (Table 2, entries 5 and
12), the lithio-ketophosphonate salt precipitated from solution
during the reaction and could be isolated directly by filtration. In
the case where direct isolation was not possible, we have shown
that the lithio-ketophosphonates can be accessed via treatment
of the ketophosphonate with LiOi-Pr/i-PrOH. These isolated salts
have a shelf life of upwards of six months without apparent
decomposition, and may be engaged directly in HWE reactions to
afford the corresponding enones in high yield (Fig. 1).
There are several notable features of the reaction that deserve
attention. The reaction is mildly exothermic upon addition of the
phosphonate to the cooled solution of LiHMDS, a sizable exotherm
is observed upon addition of the aryl ester to the mixture of Me-
PO(OR)2/LiHMDS, and a single equivalent of the MePO(OR)2 and
two equivalents of LiHMDS are sufficient to drive the reaction to
completion. The reaction can also be run at much higher tempera-
tures than with either LDA or n-BuLi, which makes it much more
amenable to large-scale application than existing approaches. Re-
cent work by Yasuda et al.3 demonstrated the instability of the Me-
PO(OR)2/LDA mixture through trapping experiments, and showed
that above À60 °C EtPO(OMe)OLi is formed through a methyl
transfer reaction. To assess the stability of the combination of Me-
PO(OR)2/LiHMDS system at elevated temperatures, we chose to
take advantage of the rapid reaction of the LiCH2PO(OMe)2 with
methyl benzoate. Thus, we incubated the MePO(OMe)2/LiHMDS
mixture at 0 °C, and then treated this mixture with methyl 2-meth-
ylbenzoate at various times (Fig. 2). The experiment highlights the
remarkable stability of this mixture, which decomposes only
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.112.
References and notes
1. Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733–1738;
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2. For the preparation of a ketophosphonate on 20 kg scale, see: Zhe-Jiang Hisun
Pharmaceutical Co. Ltd (2006) The Process and Intermediates for the Selective
Synthesis of Fluvastatin. WO Patent: 2006021326.
3. Yasuda, N.; Hsiao, Y.; Jensen, M. S.; Rivera, N. R.; Yang, C.; Wells, K. M.; Yau, J.;
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5. 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.
O
OLi
O
P
O
OMe
OMe
THF, rt
H
+
(77 %)
Br
N
N
Br
14
Figure 1. HWE reaction of isolated lithio-ketophosphonate salt with 2-bromobenzaldehyde.

872
R. R. Milburn et al. / Tetrahedron Letters 50 (2009) 870–872
6. For a recent example, see: Palacios, F.; Ochoa de Retanam, A. M.; Alonso, J. M. J.
dissolved in a minimal amount of THF) drop-wise, maintaining the internal
temperature of the reaction below 5 °C. The addition of the ester was
exothermic to varying extents depending on the reactivity of the aryl ester.
The reaction was stirred at 0 °C until complete consumption of the ester as
determined by HPLC. The mixture was partitioned between satd NH4Cl (aq)
and EtOAc, and the aqueous layer was extracted with EtOAc (1Â). The
combined organic layer was washed with water (1Â), brine (1Â), dried
(Na2SO4), and the solvent removed in vacuo.
Org. Chem. 2006, 71, 6141–6148.
7. Westermann, J.; Schneider, M.; Platzek, J.; Petrov, O. Org. Proc. Res. Dev. 2007,
11, 200–205.
8. Paterson, I.; Lyothier, I. Org. Lett. 2004, 6, 4933–4936.
9. UBE Ind. Ltd, 1996. Production of Beta-Ketophosphonate Derivative, Jpn Patent:
08099982 A.
10. Typical procedure (demonstrated on 14 mol scale): To a solution of LiHMDS
(2.2 equiv) in THF (1.0 M), cooled in an ice bath, was added methyl
dimethylphosphonate (1.1 equiv). No significant exotherm was observed
during the addition. To this mixture was added the ester (either neat or
11. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
12. The condensation of bis(trifluoroethyl) methylphosphonates with esters
mediated by LiHMDS has been demonstrated at À98 °C, see Ref. 8.