Amberlyst-15 as a heterogeneous reusable catalyst for the synthesis of α-hydroxy phosphonates in water

Article abstract of DOI:10.1055/s-2007-985595

An efficient and simple synthesis of α-hydroxy phosphonates has been achieved via reaction of aldehydes with trimethylphosphite in the presence of Amberlyst-15 in water. The reaction is highly selective with excellent yields under mild conditions. Georg T

Full text of DOI:10.1055/s-2007-985595

LETTER
2347
Amberlyst-15 as a Heterogeneous Reusable Catalyst for the Synthesis of
a-Hydroxy Phosphonates in Water
Synthesis of
a
-Hydrox
a
y Phosphon
h
ate
s
in
W
ate
m
r
ood Tajbakhsh,*a Akbar Heydari,b Mohammad A. Khalilzadeh,c Moslem M. Lakouraj,a Behi Zamenian,a
Samad Khaksarb
a
Department of Chemistry, Faculty of Basic Science, Mazandaran University, Babolsar 47415, Iran
Fax +98(11252)42002; E-mail: tajbaksh@umz.ac.ir
b
Department of Chemistry, Tarbiat Modares University, P. O. Box 14155-4838, Tehran 18716, Iran
c
Department of Chemistry, Islamic Azad University, P. O. Box 163, Qaemshahr, Iran
Received 24 May 2007
preparation of a-functionalized phosphonates, such as a-
amino,9 a-keto,10 a-halo,11 and a-acetoxyphosphonates.12
Abstract: An efficient and simple synthesis of a-hydroxy phos-
phonates has been achieved via reaction of aldehydes with tri-
methylphosphite in the presence of Amberlyst-15 in water. The
reaction is highly selective with excellent yields under mild con-
ditions.
The synthesis of a-hydroxy phosphonates has been inves-
tigated in the presence of Lewis acids,13 alumina,14 potas-
sium fluoride on alumina,15 lithium perchlorate in diethyl
ether,16 cesium fluorides,14 guanidine hydrochloride,17
quaternary ammonium hydroxide ion exchange resin,18
(R)-Al(salalen) complex,19 L-prolineamide,20 and titanium
alkoxides.21 An alternative method is the reaction of tri-
alkylphosphites with aldehydes in the presence of hydro-
gen chloride via Arbusov-like reaction of oxonium salts
derived from aldehydes or ketones.22
Key words: a-hydroxy phosphonates, Abramov reaction, water,
Amberlyst-15, nucleophilic addition
One of the fundamental and challenging goals to scientists
is to perform organic reactions in water, because water is
an environmentally friendly and safe medium, although
widely accepted as a contaminant in organic synthesis.1
Recently, water and aqueous reaction media attracted
much interest not only for the viewpoint of green chemis-
try, but also for unique physical and chemical properties
of water.2 Water also exhibits unique reactivity and selec-
tivity that cannot be attained in conventional organic sol-
vents.3 There is no doubt that the use of water as a reaction
medium could have an outstanding impact on chemical
synthesis, including at a process scale. In addition, water
is a weak electrolyte at room temperature but dissociates
to a greater extent on increasing the temperature, resulting
in higher concentrations of H3O+ and OH– at neutral con-
ditions, which can catalyze chemical reactions.4
Surprisingly, we found very few reports describing the
reaction of trialkylphosphites with aldehydes or ketones,
despite the fact that trialkylphosphites are obviously much
better nucleophiles than dialkylphosphonates, and they
are certainly P-nucleophiles because of their free electron
pairs located only on the phosphorus atom.22
Trialkylphosphites undergo the Abramov reaction only
under forcing conditions, but the replacement of one
alkoxy residue on phosphorus with a trialkylsiloxy group
increases greatly the reactivity of the resulting silyl phos-
phite ester towards unsaturated organic substrates.23
However, these methods have some disadvantages. For
example, it was found that in all studied cases, which in-
cluded aliphatic and aromatic aldehyde or ketone, the hy-
droxy phosphonates decompose to the starting carbonyl
compounds.24 In addition, the yields are not always good
and mixtures of products are sometimes obtained. Hence,
there is a need to develop a convenient, environmentally
benign, and feasible method for the synthesis of a-hy-
droxy phosphonates.
On the other hand, there has been considerable interest in
phosphorus–carbon [P–C] bond-forming reactions.5 a-
Hydroxy phosphonates which are easily prepared from
commercially available materials, have received attention
both as substrates for the preparation of other a-substitut-
ed phosphonates and because of their potential biological
activity.6 These compounds show antiviral,7a antibacteri-
al,7b antivaccinia,7c anticancer,7d pesticides,7e renin inhibi-
tors,7f HIV-protease,7g anti-HIV activities,7h,i and enzyme
inhibitor properties.7j Much of this activity has been at-
tributed to the relatively inert nature of the C–P bond and
to the physical and structural similarity of phosphonic and
phosphinic acids to the biologically important phosphate
ester and carboxylic acid functional groups.8 Furthermore,
a-hydroxy phosphonates are also useful precursors for the
In recent years, the use of solid acidic catalyst has attract-
ed considerable attention.25 In this regard, Amberlyst-15
possesses unique properties such as environmental com-
patibility, nontoxic, reusability, non-corrosive, selectivi-
ty, chemical and physical stability and can be used over a
prolonged period. Owing to the numerous advantages as-
sociated with this cheap and no hazardous catalyst, Am-
berlyst-15 has been explored as a powerful catalyst for
various organic reactions.26
SYNLETT 2007, No. 15, pp 2347–2350
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Advanced online publication: 22.08.2007
DOI: 10.1055/s-2007-985595; Art ID: D15807ST
© Georg Thieme Verlag Stuttgart · New York

2348
M. Tajbakhsh et al.
LETTER
Table 1 Synthesis of a-Hydroxy Phosphonates from Various Aldehydes
Entry
1
Aldehyde
Producta
Time (min)
90
Yield (%)b
O
OH
95
H
H
PO(OMe)2
2
3
180
225
85
O
OH
Cl
PO(OMe)2
OH
Cl
74
O
H
PO(OMe)2
Cl
Cl
4
5
150
90
80
94
OH
O
PO(OMe)2
H
O
OH
H
PO(OMe)2
PO(OMe)2
HO
HO
6
7
105
110
65
89
OH
O
H
NC
NC
O
OH
H
PO(OMe)2
MeO
MeO
8
9
120
90
85
95
OH
O
PO(OMe)2
OH
H
O
H
PO(OMe)2
10
11
12
13
170
120
120
120
75
92
90
88
OH
O
O
PO(OMe)2
H
H
OH
PO(OMe)2
OH
O
PO(OMe)2
H
O
OH
H
PO(OMe)2
14
110
80
O
OH
O
O
H
PO(OMe)2
a All the products are known compounds and were characterized by their IR, 1H NMR spectra and comparison with the authentic samples.
b All yields refer to isolated products.
Synlett 2007, No. 15, 2347–2350 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Hydroxy Phosphonates in Water
2349
(5) See for example: (a) Hanaya, T.; Sugiyama, K.; Kawamato,
H.; Yamamoto, H. Carbohydr. Res. 2003, 338, 1641.
(b) Rozhko, L. F.; Ragulun, W. Russ. J. Gen. Chem. 2005,
75, 533. (c) Yamagishi, T.; Yokomatsu, T.; Suemune, K.;
Shibuya, S. Tetrahedron 1999, 55, 12125. (d) Davies, S. R.;
Mitchell, C. P.; Cain, M. C.; Devilt, P. G.; Taylor, R. J.; Kee,
T. P. J. Organomet. Chem. 1998, 550. (e) Kralikova, A.;
Budesinky, M.; Masojidkova, M.; Rosenberg, I.
Tetrahedron 2006, 62, 4917. (f) El Kam, L.; Gaultier, L.;
Grimoud, L.; Dos Santos, A. Synlett 2005, 2335.
(g) Hudson, H. R.; Ismail, F.; Pianka, M.; Wan, C. W.
Phosphorus, Sulfur Silicon Relat. Elem. 2000, 164, 245.
(h) Conant, J. B. J. Am. Chem. Soc. 1921, 43, 1705.
(i) Failla, S.; Finocchiaro, P.; Consiglio, G. A. Heteroat.
Chem. 2000, 11, 493. (j) Dolle, R. E.; Herpin, T. F.;
Shimshock, Y. C. Tetrahedron Lett. 2001, 42, 1855.
(6) Kim, D. Y.; Wiemer, D. F. Tetrahedron Lett. 2003, 44, 2803.
(7) (a) Neyts, J.; De Clercq, E. Antimicrob. Agents Chemother.
1997, 41, 2754. (b) Fleisch, H. Endocr. Rev. 1998, 19, 80.
(c) Snoeck, R.; Holy, A.; Dewolf-Peeters, C.; Van Den
Oord, J.; De Clercq, E.; Andrei, G. Antimicrob. Agents
Chemother. 2002, 46, 3356. (d) Lee, M. V.; Fong, E. M.;
Singer, F. R.; Guenett, R. S. Cancer Res. 2001, 61, 2602.
(e) Kafarski, P.; Lejczak, B. J. Mol. Catal. B: Enzym. 2004,
29, 99. (f) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.;
Free, C. A.; Rogers, W. L.; Smith, S. A.; DeForrest, J. M.;
Oehl, R. S.; Petrillo, E. W. Jr. J. Med. Chem. 1995, 38,
4557. (g) Stowasser, B.; Budt, K. H.; Jian-Qi, L.; Peyman,
A.; Ruppert, D. Tetrahedron Lett. 1992, 33, 6625.
(h) Zheng, X.; Nair, V. Tetrahedron 1999, 55, 11803.
(i) Szymanska, A.; Szymczak, M.; Boryski, J.; Stawinski, J.;
Kraszewski, A.; Collu, G.; Sanna, G.; Giliberti, G.; Loddo,
R.; La Colla, P. Bioorg. Med. Chem. 2006, 14, 1924.
(j) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.
Tetrahedron Lett. 1990, 31, 5591.
We report here a new method for the preparation of a-hy-
droxy phosphonates from a mixture of aldehydes and tri-
methylphosphite in the presence of Amberlyst-15 in water
at 50 °C and the results are summarized in Table 1.27
When we treated benzaldehyde with trimethylphosphite
in water at 50 °C for 4 hours in the absence of Amberlyst-
15, only a low yield (<40%) of dimethyl 1-hydroxy-1-
phenylmethylphosphonate was obtained, so implying the
role of Amberlyst-15 in this reaction.
We assume that the solid acid catalyst generates hydroni-
um ion in water that activates the carbonyl group, which
consequently undergoes nucleophilic attack by trialkyl-
phosphite (Scheme 1).
H
OH
O
OH
O
H+
OMe
OMe
P(OMe)3
H2O
OMe
OMe
+
P
R
R
P
H
R
H
R
OMe
O
R = alkyl, aryl
Scheme 1
As shown in Table 1, the reaction of a mixture of aliphatic
or aromatic aldehydes and trimethylphosphite in the
presence of Amberlyst-15 in water at 50 °C, afforded the
desired products in good to high yields, after a typical
reaction time of about 1–4 hours. a,b-Unsaturated alde-
hydes also selectively afforded the corresponding a-hy-
droxy phosphonates in good yield, with no byproduct
formation. The catalyst can be regenerated simply by fil-
tration and reused several times without losing its activity.
(8) Fields, S. C. Tetrahedron 1999, 55, 12237.
(9) Kaboudin, B. Tetrahedron Lett. 2003, 44, 1051.
(10) (a) Firouzabadi, H.; Iranpoor, N.; Sobhani, S. Synth.
Commun. 2004, 34, 1463. (b) Firouzabadi, H.; Iranpoor, N.;
Sobhani, S. Tetrahedron Lett. 2002, 43, 477. (c) Kaboudin,
B.; Nazari, R. Synth. Commun. 2001, 31, 2245.
(11) Eymery, F.; Lorga, B.; Savignac, P. Tetrahedron 1999, 55,
2671.
(12) Firouzabadi, H.; Iranpoor, N.; Sobhani, S.; Amoozgar, Z.
Synthesis 2004, 1771.
(13) Evans, D. A.; Hurst, K. M.; Takacs, J. M. J. Am. Chem. Soc.
1978, 100, 3467.
(14) Texier-Boullet, F.; Foucaud, A. Synthesis 1982, 916.
(15) Texier-Boullet, F.; Lequitte, M. Tetrahedron Lett. 1986, 27,
3515.
(16) Azizi, N.; Saidi, M. R. Phosphorus, Sulfur Silicon Relat.
Elem. 2003, 178, 1255.
(17) Heydari, A.; Arefi, A.; Khaksar, S.; Tajbakhsh, M. Catal.
Commun. 2006, 7, 98.
(18) Alexander, C. W.; Albiniak, P. A.; Gibson, L. R.
Phosphorus, Sulfur Silicon Relat. Elem. 2000, 167, 205.
(19) Saito, B.; Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2007,
129, 1978.
This reaction has been performed in different organic sol-
vents such as diethyl ether, CH2Cl2, CHCl3, MeCN, THF,
dioxane, and methanol in the presence of Amberlyst-15 in
water at 50 °C and a low yield (<50%) of the a-hydroxy
phosphonates was obtained. In a similar manner, the
mixture of ketones and trimethylphosphite does not react
under these reaction conditions.
In summary, we have developed a protocol for the syn-
thesis of a-hydroxy phosphonates in the presence of
Amberlyst-15 in aqueous media.
Experimental convenience, more economic, environmen-
tally benign, good yields, and relatively clean reaction
conditions without any byproducts make this method an
attractive and a useful protocol. In many cases the prod-
ucts just crystallize directly out of the reaction mixture
and crude products are obtained in a high purity.
References and Notes
(20) Dodda, R.; Zhao, C. G. Org. Lett. 2006, 8, 4911.
(21) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron:
Asymmetry 1993, 4, 1779.
(22) (a) Goldeman, W.; Soroka, M. Synthesis 2006, 3019.
(b) Mizyuk, V. L.; Cherepanova, E. G.; Pudovik, M. A.
Zhurnal Obshchei Khimii 1980, 50, 1878.
(1) Cao, Y. J.; Lai, Y. Y.; Wang, X.; Li, Y. J.; Xiao, W. J.
Tetrahedron Lett. 2007, 48, 21.
(2) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: London, 1998.
(3) Ranu, B. C.; Banerjee, S. Tetrahedron Lett. 2007, 48, 141.
(4) Hailes, H. C. Org. Process Res. Dev. 2007, 11, 114.
(23) Sum, V.; Kee, T. P. J. Chem. Soc., Perkin Trans. 1 1993,
2701.
Synlett 2007, No. 15, 2347–2350 © Thieme Stuttgart · New York

2350
M. Tajbakhsh et al.
LETTER
(24) Gancarz, R.; Gancarz, I.; Walkowiak, U. Phosphorus, Sulfur
Silicon Relat. Elem. 1995, 104, 45.
Dimethyl1-Hydroxy-3-phenyl-2-propenylphosphonate28
(Table 1, Entry 4)
(25) Ko, S.; Yao, C.-F. Tetrahedron Lett. 2006, 47, 8827.
(26) (a) Tian, Q.; Zhang, S.; Yu, Q.; He, M.-B.; Yang, J.-S.
Tetrahedron 2007, 63, 2142. (b) Sabou, R.; Hoelderich, W.
F.; Ramprasad, D.; Weinand, R. J. Catal. 2005, 232, 34.
(c) Yadav, J. S.; Subba Reddy, B. V.; Vishnumurthy, P.
Tetrahedron Lett. 2005, 46, 1311. (d) Honkela, M. L.; Root,
A.; Lindblad, M.; Krause, A. O. I. Appl. Catal. A 2005, 295,
216.
IR: 3255 (OH) cm–1. 1H NMR (500 MHz, CDCl3): d = 3.8 (d,
JPH = 10.3 Hz, 3 H), 3.8 (d, JPH = 10.3 Hz, 3 H), 4.7 (s, OH),
6.4 (d, J = 15.9, 6.2 Hz, JPH = 5.6 Hz, 1 H), 6.8 (d, J = 15.6,
1.5 Hz, JPH = 4.9 Hz, 1 H), 7.3–7.2 (m, 3 H), 7.4–7.4 (m, 2
H). 13C NMR (500 MHz, CDCl3): d = 53.7 (d, JPC = 7.4 Hz),
53.9 (d, JPC = 7.1 Hz), 69.2 (d, JPC = 161.0 Hz), 128.4, 127.8,
126.5, 123.5 (d, JPC = 4.3 Hz), 132.2 (d, JPC = 13.0 Hz),
136.1 (d, JPC = 2.9 Hz).
(27) Typical Procedure
Dimethyl 1-Hydroxybutylphosphonate17 (Table 1, Entry
11)
A solution of benzaldehyde (0.107 g, 1 mmol), trimethyl-
phosphite (0.136 g, 1.1 mmol), and Amberlyst-15 (0.1 g) in
H2O (2 mL) was placed in a round-bottomed flask equipped
with a magnetic stirrer and was heated at 50 °C. The stirring
was continued for 1.5 h. After completion of the reaction as
indicated by TLC, the reaction mixture was treated with aq
sat. NaHCO3 solution followed by brine and the product was
extracted three times with 5 mL CH2Cl2, dried over anhyd
MgSO4, and concentrated to give an oily residue, which was
crystallized to give 0.216 g (95%) of dimethyl 1-hydroxy-1-
phenylmethylphosphonate.
IR: 3312 (OH) cm–1. 1H NMR (90 MHz, CDCl3): d = 1.0 (t,
3 H), 1.8–1.1 (m, 4 H), 2.7 (m, 1 H), 3.7 (d, 3JPH = 5.4 Hz, 3
H), 3.8 (d, 3JPH = 5.4 Hz, 3 H), 3.9 (s, OH). 13C NMR (22.5
MHz, CDCl3): d = 13.8 (d, 4JPC = 19.1 Hz, CH3), 19.9 (d,
3JPC = 11.8 Hz, CH2), 29.0 (d, 2JPC = 7.4 Hz, CH2), 51.1 (d,
2JPC = 7.3 Hz, OCH3), 52.2 (d, 2JPC = 7.3 Hz, OCH3), 56.8
(d, 1JPC = 136.8 Hz, OCH3).
Dimethyl 1-Hydroxy-2-methylpropylphosphonate17
(Table 1, Entry 13)
IR: 3313 (OH) cm–1. 1H NMR (90 MHz, CDCl3): d = 0.8 (m,
3 H), 1.9 (m, 1 H), 3.6 (m, 1 H), 3.6 (d, 3JPH = 4.4 Hz, 3 H),
3.7 (d, 3JPH = 4.4 Hz, 3 H), 4.8 (s, O H). 13C NMR (22.5
MHz, CDCl3): d = 17.4 (d, 4JPC = 7.0 Hz, CH3), 19.4 (d,
3JPC = 9.5 Hz, CH2), 29.9 (d, 2JPC = 8.0, CH), 52.4
(2JPC = 6.5 Hz, OCH3), 52.6 (2JPC = 6.5 Hz, OCH3), 73.2
(1JPC = 148.4 Hz, CH).
Spectral Data for Selected Products
Dimethyl 1-Hydroxy-1-phenylmethylphosphonate19
(Table 1, Entry 1)
IR: 3260 (OH) cm–1. 1H NMR (500 MHz, CDCl3): d = 3.6 (d,
J = 10.3 Hz, 3 H), 3.6 (d, J = 10.3 Hz, 3 H), 5.0 (d, 1 H,
J = 13.2 Hz), 6.0 (s, OH), 7.3–7.5 (m, 5 H). 13C NMR (125
MHz, CDCl3): d = 53.7 (d, JCP = 7.5 Hz), 54.2 (d, JCP = 7.5
Hz), 69.1 (d, JCP = 164.0 Hz), 128.8, 129.4, 131.1, 133.8 (d,
Dimethyl 1-Hydroxy-1-furylmethylphosphonate17
(Table 1, Entry 14)
J
CP = 2.9 Hz).
1H NMR (90 MHz, CDCl3): d = 1.3 (s, OH), 3.7 (d,
3JPH = 5.8 Hz, 3 H), 3.9 (d, 3JPH = 5.8 Hz, 3 H), 5.0 (d,
2JPH = 13.5 Hz, 1 H), 6.4–6.6 (m, 2 H), 7.4 (s, 1 H). 13C NMR
(22.5 MHz, CDCl3): d = 53.6 (d, 2JPC = 2.7 Hz, OCH3), 53.9
(d, 2JPC = 2.7 Hz, OCH3), 64.2 (d, 1JPC = 167.8 Hz, CH),
109.3 (d, 3JPC = 6.4 Hz, C), 110.7 (s, CH), 142.8 (d,
3JPC = 1.8 Hz, CH), 149.9 (s, CH).
Dimethyl 1-Hydroxy-1-(4-chlorophenyl)methyl-
phosphonate19 (Table 1, Entry 3)
IR: 3290 (OH) cm–1. 1H NMR (500 MHz, CDCl3): d = 3.6–
3.7 (m, 6 H), 5.1 (d, J = 13.4 Hz, 1 H), 6.2 (s, OH), 7.4 (d,
J = 8.5 Hz, 2 H), 7.5 (d, J = 8.5 Hz, 2 H). 13C NMR (125
MHz, CDCl3): d = 53.7 (d, JCP = 7.1 Hz), 54.2 (d, JCP = 7.5
Hz), 69.1 (d, JCP = 161.1 Hz), 128.8, 129.4, 133.1 (d,
(28) He, A.; Yan, B.; Thanavaro, A.; Spilling, C. D.; Rath, N. P.
J. Org. Chem. 2004, 69, 8643.
JCP = 3.9 Hz), 138.2.
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