Catalytic synthesis of α-hydroxyphosphonates

Article abstract of DOI:10.1134/S1070428009080016

Reactions of carbonyl compounds of aliphatic, aromatic, and heteroaromatic series with dialkyl phosphites in the presence of DBN were studied under microwave irradiation.

Full text of DOI:10.1134/S1070428009080016

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 8, pp. 1119−1122. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © M.M. Kabachnik, L.I. Minaeva, I.P. Beletskaya, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 8,
pp. 1135−1137.
Catalytic Synthesis of α-Hydroxyphosphonates
M. M. Kabachnik, L. I. Minaeva, and I. P. Beletskaya
Lomonosov Moscow State University, Moscow, 119899 Russia
e-mail: mariamk@mail.ru
Received September 24, 2008
Abstract—Reactions of carbonyl compounds of aliphatic, aromatic, and heteroaromatic series with dialkyl
phosphites in the presence of DBN were studied under microwave irradiation.
DOI: 10.1134/S1070428009080016
The reaction of dialkyl phosphites (Abramov reaction)
leading to the formation of hydroxyphosphonates is
commonly known. Although the reaction has been dis-
covered at the beginning of nineteen fifties [1], it still
attracts the interest of chemists [2, 3], evidently due firsts
of all to the practical applications of α-hydroxyphos-
phonates.
Aiming at the optimization of the preparation conditions
for α-hydroxyphosphonates we investigated the reaction
of dialkyl phosphates with carbonyl compounds of
aliphatic, aromatic, and heteroaromatic series in the
presence of 1,5-diazabicyclo-[4.3.0.]non-5-ene (DBN)
under the microwave irradiation. The application of micro-
wave irradiation (MW) for acceleration of organic, and
in particular, organophosphorus, processes is well known
[13–17].
Among the functionally substituted phosphonic acids
α-hydroxyphosphonic acids and their esters possess
a special place for they are endowed with a wide range
of biological action: from antibacterial, neuroactive , and
anticancer drugs to enzymes inhibitors and pesticides [4–
8]. The biological activity of this class of organophos-
phorus compounds originates from their structural analogy
to α-hydroxycarboxylic acids; they exhibit a wide inhibitor
effect with respect to enzymes and receptors that usually
bind the natural α-hydroxycarboxylic acids [9].
The reactions of dialkyl phosphates with carbonyl
compounds are commonly carried out in the presence of
a basic catalyst that displaces the tautomeric equilibrium
of the dialkyl phosphite to the three-coordinated form.
The usually applied catalysts are metal alcoholates,
tertiary amines, or inorganic bases taken in equimolar
amounts or in excess. However the reaction in the
presence of a large quantity of bases is often accompanied
by the partial decomposition of the obtained α-hydroxy-
phosphonates (retro-Abramov reaction) [10, 11], or by
the formation of the corresponding phosphates [12]. In
this connection the search for new active catalysts and
optimum conditions for performance ofAbramov reaction
is still topical nowadays.
The combination of catalysis by DBN and MW
assistance made it possible to obtain α-hydroxyphos-
phonates quickly (in several minutes) and in high yields.
The reaction of carbonyl compounds of aliphatic,
aromatic, and heteroaromatic series Ia–Ij with dialkyl
phosphates was carried out under the action of the
microwave irradiation without solvent in the presence of
1 mol% of DBN. The monitoring of the reaction progress
was performed by 31P NMR, IR spectroscopy, and also
by TLC (Silufol plates, eluent chloroform–methanol, 10:1).
As show the data of 31PNMR spectroscopy, the reactions
of aldehydes and ketones Ia–Ih with diethyl phosphite
under these conditions proceed materially quantita-
tively.
At the use of aldehydes the yield of the final products
is insignificantly affected by the aldehyde structure
whereas with ketones the reaction under study occurs
easily only with cyclohexanone (Ih), yet with
cyclopentanone (Ii) and methyl ethyl ketone (Ij) even at
longer heating the corresponding α-hydroxyphosphonates
are formed only in ~40% yield.
1119

KABACHNIK et al.
1120
R1
R2
catalysis with DBN and with microwave irradiation
provided a possibility to obtain α-hydroxyphosphonates
of versatile structure quickly and in high yields.
(EtO) P(O)H
+
O
2
Iа_Ij
1 mol% DBN, MW
EXPERIMENTAL
R1
1H, 13C, and 31P NMR spectra were registered on
a spectrometer Bruker Avance-400 (at operating frequ-
encies 400, 100.6, 161.9 MHz respectively). The chloro-
form signal was used as internal reference (δH 7.24, δC
77.10 ppm). The melting points were measured on an
Electrothermal 9100 instrument. The reaction progress
was monitored and the purity of chemical compounds
was checked by TLC (Silufol UV-254). The preparative
column chromatography was carried out using silica gel
Merck (40/60).
OH
R2
P(O)(OEt)2
IIа_IIj
R1 = H, R2 = Et (a), i-Pr (b), Ph (c), m-NO2C6H4 (d),
p-ClC6H4 (e), 2-Fur (f), 2-Pyr (g); R1,R2 = cyclo-C6H10 (h),
cyclo-C5H8 (i), R1 = Me, R2 = Et (j).
The application of 1 mol% of DBN combined with
MW assistance not only provided high yields of
hydroxyphosphonates, but also prevented the side
processes. The addition of a larger amount of the catalyst
(2 mol% and more) at MW irradiation resulted in the
reduced product yield due to the phosphate formation by
the phosphonate-phosphate rearrangement.
Synthesis of α-hydroxyphosphonates under the
microwave assistance. General procedure. To 0.01 mol
of O,O-dialkyl phosphite was added in succession
0.0001 mol of 1,5-diazabicyclo[4.3.0.]non-5-ene (DBN)
and 0.01 mol of carbonyl compound Ia–Ij, IIIa, and IIIb.
The reaction was performed at microwave irradiation
(400 W, 180°C). The reaction mixture was distilled in
a vacuum. In event of formation of solid compounds the
α-hydroxyphosphonate was isolated by column
chromatography (silica gel, eluent chloroform–methanol,
10:1).
The reaction at room temperature on at heating (40–
45°C) proceeded considerably slower. For instance, the
reaction of benzaldehyde with diethyl phosphite in the
presence of 1 mol% of DBN proceeded at heating for 6
h, and α-hydroxyphosphonate IIc formed in 44% yield.
The addition of chiral dialkyl phosphites (dimenthyl
phosphite) to aromatic and aliphatic aldehydes at the
catalysis with DBN and microwave irradiation led to the
formation of α-hydroxyphosphonate (according to 31
Diethyl (1-hydroxypropyl)phosphonate (IIa).
Reaction time 1 min. Yield 1.9 g (95%), bp 92–95°C
(2 mm Hg). 31P NMR spectrum (CDCl3): δ 25.6 ppm [1].
P
NMR data) with a slight stereoselectivity (the
diastereomers ratio ~1:1.2). The yields of the
corresponding final compounds in these cases are virtually
quantitative.
Diethyl (1-hydroxy-2-methylpropyl)phosphonate
(IIb). Reaction time 1.5 min. Yield 2.1 g (98%), bp 115–
118°C (3 mm Hg). 31P NMR spectrum (CDCl3):
δ 25.3 ppm [18].
Diethyl [hydroxy(phenyl)methyl]phosphonate
(IIc). Reaction time 3 min. Yield 2.1 g (86%), mp 82–
84°C. 31P NMR spectrum (CDCl3): δ 21.7 ppm [1].
R1
(MntO) P(O)H
+
O
2
R2
Diethyl [hydroxy(3-nitrophenyl)methyl]phos-
phonate (IId). Reaction time 3.5 min. Yield 2.4 g (85%),
mp 93–95°C. 31P NMR spectrum (CDCl3): δ 20.1 ppm
[19].
IIIa, IIIb
R1
1 mol% DBN, MW
OH
P(O)(OMnt)2
IVa, IVb
R2
Diethyl [hydroxy(4-chlorophenyl)methyl]phos-
phonate (IIe). Reaction time 9 min. Yield 2.2 g (82%).
1
Oily substance. H NMR spectrum (CDCl3), δ, ppm:
1.24 t (3H, OCH2CH3, 2J 7.1 Hz), 1.30 t (3H, OCH2CH3,
2J 7.1 Hz), 4.14 m (4H, OCH2CH3), 5.01 d (1H, CHP,
Mnt = (–)-menthyl; R1 = H, R2 = i-Pr (a), Ph (b).
2
2J 13.4 Hz), 7.55 t (1H, CHCHCH, J 7.7 Hz), 6.36 t
Thus we showed that the performance of the reaction
of carbonyl compounds with dialkyl phosphates under the
2
[2H, CHCHC(CHOH), J 7.7 Hz], 6.50 d (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 8 2009

CATALYTIC SYNTHESIS OF α-HYDROXYPHOSPHONATES
1121
ClCCHCHCH, 2J 7.7 Hz). 13C NMR spectrum (CDCl3),
δ, ppm: 16.24 s (OCH2CH3), 63.00 s, 63.43 s
31.61 s [CH(CH3)2], 34.05 s, 34.16 s (CHCH2CH),
43.10 s, 42.22 s [CHCH2CHC(CH3)2]; 43.72 s, 43.79 s
[CHCHC(CH3)2], 73.62 d, 74.00 d (PCHN, 1JCP 156.7,
1JCP 155.4 Hz), 77.87 s, 78.00 s (POCH2). 31P NMR
spectrum (CDCl3), δ, ppm: 23.69, 23.90 Found, %: C 68.97;
H 14.52. C24H39O4P. Calculated, %: C 68.22; H 15.15.
1
(OCH2CH3), 69.81 s (PCN, JCP 162.2 Hz), 128.15 s,
128.41 s, 128.49 s, 131.35 s, 133.59 s, 135.57 s (C6H5).
31P NMR spectrum (CDCl3): δ 21.2 ppm.
Diethyl [hydroxy(2-furyl)methyl]phosphonate
(IIf). Reaction time 1.5 min. Yield 2.4 g (95%), bp 182–
185°C (3 mm Hg). 31P NMR spectrum (CDCl3):
δ 19.6 ppm [20].
Di(–)-menthyl [hydroxy(phenyl)methyl]phos-
phonate (IVb). Reaction time 19 min. Yield 4.2 g (92%),
1
mp 95–98°C. H NMR spectrum (CDCl3), δ, ppm: 0.74–
0.81 m (6H, CH3CCH3 for two diastereomers), 1.11–
1.15 m [4H, CHCH2CHC(CH3)2], 1.28–1.31 m (6H,
CH3CCH3 for two diastereomers), 1.61–1.66 m [4H,
CHCH2CHC(CH3)2], 2.00–2.04 m (8H, CHCH2CH, for
two diastereomers), 2.24–2.27 m (4H, CH2CHCH2 for
two diastereomers), 2.70–2.74 m [4H, CHCHC(CH3)2
for two diastereomers], 4.22– 4.25 m (8H, POCH2 for
two diastereomers), 4.94–4.97 m (2H, PCHN, for two
diastereomers), 5.35–5.42 m [4H, CCHCHC(CH3)2 for
two diastereomers], 7.36–7.61 m (10H, C6H5, for two
diastereomers). 13C NMR spectrum (CDCl3) (for two
diastereomers), δ, ppm: 21.93 s, 25.27 s (CH3CCH3),
31.47 s, 31.59 s [CH2CHC(CH3)2], 33.98 s, 34.05 s
(CHCH2CH), 42.58 s, 42.82 s [CHCH2CHC(CH3)2],
43.69 s, 43.92 s [CHCHC(CH3)2], 69.01 d, 71.67 d
Diethyl [hydroxy(2-pyridyl)methyl]phosphonate
(IIg). Reaction time 5 min. Yield 2.0 g (82%), mp 59–
1
61°C. H NMR spectrum (CDCl3), δ, ppm: 1.26 t (3H,
OCH2CH3, 2J 6.6 Hz), 1.35 t (3H, OCH2CH3,2J 6.6 Hz),
2
4.23 d (2H, OCH2CH3, J 7.3 Hz), 4.29 d (2H,
2
OCH2CH3, 2J 7.3 Hz), 5.91 d (1H, CHP, J 17.9 Hz),
7.86–8.95 m (4H, C5H4N). 13C NMR spectrum (CDCl3),
δ, ppm: 16.42 s (OCH2CH3), 64.37 s (OCH2CH3), 67.33
1
d (PCN, JCP 164.7 Hz), 125.47 s, 125.92 s, 141.55 s,
144.88 C, 154.02 s (C5H4N). 31P NMR spectrum
(CDCl3): δ 15.7 ppm.
Diethyl (1-hydroxycyclohexyl)phosphonate (IIh).
Reaction time 4 min. Yield 1.9 g (84%), mp 74–76°C.
31P NMR spectrum (CDCl3): δ 26.8 ppm [1].
Diethyl (1-hydroxycyclopentyl)phosphonate (IIi).
Reaction time 15 min. Yield 0.7 g (40%), mp 71–73°C.
31P NMR spectrum (CDCl3): δ 27.2 ppm [1].
Diethyl (1-hydroxy-1-methylpropyl)phosphonate
(IIj). Reaction time 21 min. Yield 0.8 g (38%). Oily
substance. 31P NMR spectrum (CDCl3): δ 27.8 ppm
[21].
1
1
(PCHN, JCP 152.8, JCP 158.7 Hz), 78.26 s, 78.57 s
(POCH2), 127.31 s, 127.41 s [CCHCHC(CH3)2],
127.16 s, 127.89 s, 128.10 s (C6H5). 31P NMR spectrum
(CDCl3), δ, ppm: 19.88, 20.32. Found, %: C 70.87; H 8.23.
C27H37O4P. Calculated, %: C 71.03; H 8.17.
The study was carried out under the financial support
of the Russian Foundation for Basic Research (grant no.
08-03-00178).
Di(–)-menthyl (1-hydroxy-2-methylpropyl)phos-
phonate (IVa). Reaction time 10 min. Yield 4.0 g (94%).
1
Oily substance. H NMR spectrum (CDCl3), δ, ppm:
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