PAPER
A Convenient Preparation of Difficultly Accessible sec-Alkylmethylphosphinates
1929
(120 mL) the mixture was filtered, the EtOAc phase washed with
sat. aq NaHCO3 solution (30 mL) and brine (30 mL), dried
(Na2SO4) and evaporated in vacuo to give a colorless oil (1.94 g,
~100%). The oil (1.94 g, 6.3 mmol), AIBN (0.29 g, 1.6 mmol), and
Bu4SnH (1.68 g, 9.5 mmol) were dissolved in anhyd toluene (40
mL) under N2 and heated to 90°C for 5.5 h. The solution was evap-
orated in vacuo, and the product was purified by flash chromatogra-
phy using 8% MeOH in CH2Cl2 as eluent to give the pure 6d as a
colorless oil (0.81 g, 72%) (Table 2).
sec-alkylmethylphosphinates dealkylated by trimethylsi-
lyl bromide or refluxing in hydrochloric acid. This is a
convenient route to a variety of sec-alkylmethylphosphi-
nates, which are difficult to prepare by other methods.
This method for the syntheses of sec-alkylmethylphos-
phinates seems to be quite general and can also be used for
the syntheses of other phosphinic acids and phosphonic
acids in good yields.53 In addition, the developed reaction
conditions are rather mild and many different functional
groups can be tolerated without compromising yields.
References
(1) Dingwall, J. G. Phosphorus and Sulfur 1983, 18, 353.
(2) Dingwall, J. G.; Ehrenfreund, J.; Hall, R. G. Tetrahedron
1989, 45, 3787.
(3) Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J. Chem. Soc.,
Perkin Trans 1 1984, 2845.
(4) Drysdale M. J.; Pritchard, M. C.; Horwell, D. C. J. Med.
Chem. 1992, 35, 2573.
(5) Dher, P. S.; Mathur, A.; Fischer, L. G.; Wu, G.; Skwish, S.;
Michel, I. M.; Seiler, S. M.; Dickinson, K. E. J. Bioorg. Med.
Chem. Lett. 1997, 7, 1583.
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Bernasconi, R.; Gentsch, C.; Hauser, K.; Jaekel, J.; Karlsson,
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Schmutz, M.; Steinmann, M. W.; Riezen, van H.; Vassout, A.;
Mondadori, C.; Olpe, H-R.; Waldmeier, P. C.; Bittiger, H. J.
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(7) Froestl, W.; Mickel, J. S.; Hall, R. G.; Sprecher, von G.; Strub,
D.; Baumann, P. A.; Brugger, F.; Gentsch, C.; Jaekel, J.; Olpe,
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Ketones, Et3N, tributyltin hydride, methyl oxalyl chloride,
azoisobutyronitrile (AIBN) and lithium diisopropylamide (2 M in
THF) were from Fluka. Methyldichlorophosphine was from
Hoechst. All other reagents were from Aldrich. Ethyl methylphos-
phinate (2)50 was prepared by a known literature method.51 Solvents
were HPLC grade from LAB-SCAN and were dried over molecular
sieves (4 Å). Column chromatography was run on Merck 9385 sili-
ca gel 60 (0.040–0.063 mm). 31P NMR spectra were recorded on a
Varian Unity 300 MHz spectrometer, 1H NMR and 13C NMR spec-
tra on a Varian Unity 400 MHz spectrometer, FAB MS data were
obtained using a JEOL HX 110/110 Mass Spectrometer.
Ethyl (N-Ethoxycarbonyl-4-hydroxypiperidin-4-yl)meth-
ylphosphinate (3b); Typical Procedure for Pudovik Addition
A m i n e - C a t a l y z e d : N-Ethoxycarbonylpiperid-4-one (8.6 g,
50 mmol), ethyl methylphosphinate (2; 9.8 g, 50 mmol) and anhyd
Et3N (7.0 mL, 50 mmol) were heated under N2 to 100°C for 2 h. The
mixture was cooled to 30 °C and anhyd Et2O (40 mL) was added
with stirring. The mixture was cooled to 0°C. The colorless crystals
formed were filtered, washed with anhyd Et2O (2 x 6 mL) and dried
in vacuo (Table 1).
(8) Murata, Y.; Woodward, R. M.; Miledi, R.; Overman, L. E.
Bioorg. Med. Chem. Lett. 1996, 6, 2073.
L D A - P r o m o t e d : E t h y l m e t h y l p h o s p h i n a t e ( 2; 9.8
g, 50 mmol) was dissolved in anhyd THF (50 mL) under N2 and
cooled to –78°C. LDA (2 M in THF; 25 mL, 50 mmol) was added
under N2 during 15 min. The mixture was stirred 5 min at –78 °C,
the ketone added in one portion and the mixture allowed to warm to
r.t. The mixture was quenched by addition of sat. aq NH4Cl solution
(50 mL), the THF evaporated in vacuo and the mixture extracted
with CH2Cl2 (2 × 50 mL). The organic phase was dried (Na2SO4)
evaporated in vacuo and the crystallized product washed with cold
Et2O (2 × 15 mL) (Table 1).
(9) Fagg, G. E.; Lanthorn, T. H. Br. J. Pharmacol. 1985, 86, 743.
(10) Hays, S. J.; Bigge, C. F.; Novak, P. M.; Drummond, J. T.;
Bobovski, T. P.; Rice, M. J.; Johnson, G.; Brahce, L. J.;
Coughenour, L. L. J. Med. Chem. 1990, 33, 2916.
(11) Rowley, G. L.; Greenleaf, A. L.; Kenyon, G. L. J. Am. Chem.
Soc. 1971, 93, 5542.
(12) Sosnovsky, G.; Lukszo, J.; Gravela, E.; Zuretti, M. F. J. Med.
Chem. 1985, 28, 1350.
(13) Cowart, M.; Kowaluk, E. A.; Kohlhass, K. L.; Alexander, K.
M.; Kerwin Jr., J. F. Bioorg. Med. Chem. Lett. 1996, 6, 999.
(14) Caldwell, C. G.; Sahoo, S. P.; Polo, S. A.; Eversole, R. R.;
Lanza, T. J.; Mills, S. G.; Niedzwiecki, L. M.; Izquerdo-
Martin, M.; Chang, B. C.; Harrison, R. K.; Kuo, D. W.; Lin,
T.-Y.; Stein, R. L.; Durette, P. L.; Hagmann, W. K Bioorg.
Med. Chem. Lett. 1996, 6, 323.
(15) Pikul, S.; McDow Dunham, K. L.; Almstead, N. G.; De B
Natchus, M. G.; Anastasio, M. V.; McPhail, S. J.; Snider, C.
E.; Taiwo, Y. O.; Chen, L.; Dunaway, C. M.; Gu, F.; Mieling,
G. E. J. Med. Chem. 1999, 42, 87.
(16) Logusch, E. W.; Walker, D. M.; McDonald, J. F.; leo, G. C.;
Franz, J. E. J. Org. Chem. 1988, 53, 4069.
(17) Maier, L.; Rist, G.; Lea, P. J. Phosphorus and Sulfur 1983, 18,
349.
(18) Zeiss, H-J. J. Org. Chem. 1991, 56, 1783.
(19) Walker, D. M.; McDonald, J. F.; Franz, J. E.; Logusch, E. W.
J. Chem. Soc., Perkin Trans 1 1990, 659.
(20) Bayer, E.; Gugel, K. H.; Hägele, K.; Hagenmeier, H.;
Jessipow, S.; König, W. A.; Zähner, H. Helv. Chim. Acta
1972, 55, 224.
Ethyl (1-Hydroxy-1-phenylethyl)methylphosphinate (3g); Typ-
ical Procedure for Silyl-Abramov Reaction
Ethyl methylphosphinate (2; 1.08 g, 10 mmol), acetophenone (1.20
g, 10 mmol) and hexamethyldisilazane were mixed under N2 and
heated to 90 °C until analysis by 31P NMR spectroscopy showed
complete conversion to the TMS-protected product (27 h). After
cooling to r.t., MeCN (10 mL) and Et3N•3HF (0.53 g, 4.0 mmol)
were added and heated to 40 °C. After 24 h CH2Cl2 (100 mL) was
added, the mixture washed with satd aq NaHCO3 solution (30 mL),
0.1 M HCl (30 mL), and brine (50 mL). Each aqueous phase was
back-extracted with CH2Cl2 (50 mL), and the combined organic
phases were evaporated in vacuo to give 3g as white crystals (1.54
g, 68%) (Table 1).
Ethyl (1-Propylbutyl)methylphosphinate (6d); Typical Proce-
dure for Barton–McCombie Reaction
Ethyl (1-hydroxy-1-propylbutyl)methylphosphinate (3d; 1.40 g, 6.3
mmol) and 4-(dimethylamino)pyridine (1.40 g, 11.4 mmol) were
dissolved in anhyd MeCN (10 mL) under N2 and cooled to 0 °C.
Methyl oxalyl chloride (1.15 g, 9.4 mmol) was added and the mix-
ture allowed to warm to 23 °C for 2.5 h. After addition of EtOAc
(21) Borloo, M.; Jiao, X-Y.; Wojtowicz, H.; Rajan, P.;
Verbruggen, C.; Augustyns, K.; Haemers, A. Synthesis 1995,
1074.
Synthesis 1999, No. 11, 1925–1930 ISSN 0039-7881 © Thieme Stuttgart · New York