A simple method of β-Aminophosphonates synthesis

Full text of DOI:10.1134/S1070363209120275

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 12, pp. 2705–2706. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © E.V. Grishkun, O.I. Kolodyazhnyi, 2009, published in Zhurnal Obshchei Khimii, 2009, Vol. 79, No. 12, pp. 2067–2068.
LETTERS
TO THE EDITOR
A Simple Method of β-Aminophosphonates Synthesis
E. V. Grishkun and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
Murmanskaya ul. 1, Kiev, 02094 Ukraine
fax: 38(044)573-2555
e-mail: olegkol321@rambler.ru
Received April 22, 2009
DOI: 10.1134/S1070363209120275
RO
RO
We developed a simple two-stage synthesis of amino-
phosphonates containing an unsubstituted amino group,
whose synthesis by other methods was a complex
problem [1, 2]. Diethyl methylphosphonate was treated
by butyllithium in THF, after which it was reacted with
nitriles to form β-enaminophosphonates Ia–Id in high
yields as we have described previously [3]. Then β-
enaminophosphonates I were reduced with calcium boro-
hydride in the THF-isopropanol or THF-aqueous ethanol
mixture to give β-aminophosphonate II in high yield.
Calcium borohydride was obtained by the reaction of
sodium borohydride with calcium chloride in THF. In
the mixture THF-aqueous ethanol this reaction pro-
ceeded more rapidly. However, besides aminophos-
phonate, ketophosphonate admixture formed (~10%),
which was easily separated by extraction with ethyl
acetate after acidification of the reaction mixture by
hydrochloric acid where the aminophosphonate exists
as hydrochloride. Free aminophosphonate was isolated
after the reaction mixture was neutralized with alkali.
Aminophosphonates were purified by vacuum distilla-
tion, and they were isolated as colorless viscous liquids.
Purity and structure of aminophosphonates II were
(1) BuLi
(2) R'CN
NH2
P
(RO)2P(O)Me
R'
Ia_Ic
O
RO
RO
RO
RO
Ca(BH4)2
NH2
R'
O
P
P
R'
O
O
IIIa_IIIc
IVa
R = Me, R' = Ph (а), R = Et, R' = Furyl (b): R = Et, R' =
C6H4OCHF2 (c).
0.38 g (10 mmol) of sodium borohydride. This mixture
was stirred for 8 h at room temperature. Then the
reaction mixture was kept overnight. To the reaction
mixture was added 10 ml of saturated solution of citric
acid under stirring till the precipitate completely
dissolved. Thereafter 5 more drops of concentrated
hydrochloric acid were added. Then the reaction
medium was alkalinized by adding aqueous solution of
sodium carbonate. The amine was extracted with ethyl
acetate (3 × 5 ml). The combined extracts were washed
with the saturated solution of sodium chloride (3 ×
3 ml), dried with anhydrous sodium sulfate, filtered,
and concentrated. The residue was distilled in a
vacuum. Yield 0.75 g (67%), bp 155°С (0.05 mm Hg),
Rf 0.08 (ethyl acetate). 1Н NMR spectrum (CDCl3), δH,
ppm: 2.13 m (1H, PCH2), 2.18 m (1H, PCH2), 2.78 br
(2H, NH2), 3.7 d (3H, CH3O, J 11 Hz), 3.68 d (3H,
CH3O, J 11 Hz), 4.41 m (1H, CHN), 7.3–7.4 m (5H,
C6H5). 31Р NMR spectrum (CDCl3), δP, ppm: 31.34.
Found, %: N 6.15; P 13.50. C10H16NO3P. Calculated,
%: N 6.11; P 13.54.
1
confirmed by TLC, Н, 19F, and 31Р NMR spectro-
scopy. In the 31P NMR spectrum the chemical shifts δP
1
were displaced to 30 ppm. The Н NMR spectra
contain a doublet signal of the two protons of PCH2
group; protons of amino group appear as a broad signal
at 2.5 ppm.
Dimethyl (2-amino-2-phenyl)ethylphosphonate
(IIa). To a solution of 1.43 g (5 mmol) of enamine Ia,
obtained as it is described in [1], in the mixture 6 ml of
anhydrous 2-propanol and 3 ml of THF was added
0.56 g (5 mmol) of anhydrous calcium chloride and
2705

2706
GRISHKUN, KOLODYAZHNYI
(CDCl3), δP, ppm: 28.7. Found, %: N 5.62; P 12.55.
Diethyl [2-amino-2-(2-furyl)]ethylphosphonate
(IIb). a. It was obtained similarly. Yield 67%, bp 142–
C10H17NO4P. Calculated, %: N 5.69; P 12.60.
145°С (0.05 mm Hg), Rf 0.11 (ethyl acetate).
Diethyl 2-amino-2-[4-(difluoromethoxy)phenyl]-
ethylphosphonate (Ic) was obtained similarly
(method b). Yield 60%, bp 160°С (0.08 mm Hg), Rf
b. To a solution of 5 mmol of enamine Ib obtained
as it is described in [3] in a mixture of 6 ml of ethanol,
3 ml of THF, and 1 ml of water was added 5 mmol of
anhydrous calcium chloride and 10 mmol of sodium
borohydride. This mixture was stirred for 6 h at room
temperature. Then 10 ml of saturated solution of citric
acid was added to the reaction mixture till the
precipitate completely dissolved. Thereafter hydro-
chloric acid was added to pH = 1 according to the
indicator paper. The reaction mixture was washed with
ethyl acetate, in which diethyl 2-oxo-2-phenylethyl-
phosphonate IIIb was found after evaporating [3].
Then the reaction mixture was neutralized by alkali to
the strong basic reaction medium. The amino-
phosphonate was extracted with ethyl acetate (3 ×
5 ml). Extracts were washed with the saturated
solution of sodium chloride (3 × 3 ml), dried with
anhydrous sodium sulfate, filtered, and concentrated.
The residue was distilled in a vacuum. Yield 68%, bp
1
0.07 (ethyl acetate). Н NMR spectrum (CDCl3), δН,
ppm: 1.34 t (6H, CH3, J 7 Hz), 2.13 m (1H, PCH2),
2.18 m (1H, PCH2), 2.78 br (2H, NH2), 4.08 m (4H,
OCH2), 4.41 m (1H, CHN), 6.6 t (1H, OCHF2, J 73
Hz), 7.0–7.6 m (4H, C6H4). 31Р NMR spectrum
(CDCl3), δР, ppm: 29.0. Found, %: F 11.75; N 4.33; P
9.58. C13H20F2NO4P. Calculated, %: F 11.77; N 4.33;
P 9.60.
The NMR spectra were registered on a Varian-300
instrument relative to internal ТМS (1Н and 13С) and
85% Н3РО4 in D2O (31Р). This work was supported by
the grant STCU no. 3558.
REFERENCES
1. Aminophosphonic and Aminophosphinic Acids. Chem-
istry and Biological Activity, Kukhar, V.P. and Hud-
son, H.R., Eds., New York : John Wiley, 2000, p. 1.
1
142–145°С (0.05 mm Hg), Rf 0.11 (ethyl acetate). Н
NMR spectrum (CDCl3), δH, ppm: 1.3 t (3H, CH3CH2,
J 7 Hz), 1.93 br (2H, NH2), 2.15 m (1H, PCH2), 2.32 m
(1H, PCH2), 4.1 m (4H, OCH2), 4.4 m (1H, CHN),
2. Engel, R., Phosphorus Addition at sp2 Carbon. Organic
Reactions, New York: Wiley Int., 1988, vol. 50, p. 176.
3. Grishkun, E.V. and Kolodyazhnyi, O.I., Zh. Obshch.
Khim., 2009, vol. 79, no. 12, p. 2065.
31
6.18 m, 6.3 m, 7.34 m (3H, furyl). Р NMR spectrum
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 12 2009