New access to H-phosphonates via metal-catalyzed phosphorus-oxygen bond formation

Article abstract of DOI:10.1016/j.tetlet.2007.07.057

A novel approach to H-phosphonates from hypophosphorous acid using a transfer hydrogenation process was developed. This method is atom-economical, environmentally friendly, catalytic, and efficient, leading easily to H-phosphonate monoesters or ammonium s

Full text of DOI:10.1016/j.tetlet.2007.07.057

Tetrahedron Letters 48 (2007) 6505–6508
New access to H-phosphonates via metal-catalyzed
phosphorus–oxygen bond formation
Lae¨titia Coudray, Isabelle Abrunhosa-Thomas and Jean-Luc Montchamp*
Department of Chemistry, Texas Christian University, Box 298860, Fort Worth, TX 76129, USA
Received 21 June 2007; revised 9 July 2007; accepted 9 July 2007
Available online 13 July 2007
Abstract—A novel approach to H-phosphonates from hypophosphorous acid using a transfer hydrogenation process was
developed. This method is atom-economical, environmentally friendly, catalytic, and efficient, leading easily to H-phosphonate
monoesters or ammonium salt in moderate to good yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
H-Phosphonate monoesters (1) are important synthetic
intermediates in general phosphorus chemistry1 but
mostly in the synthesis of phosphates. Phosphate groups
are present in numerous biological molecules such as
nucleic acids, proteins, carbohydrates, lipids, coenzymes,
and steroids. Therefore, in order to study biological
pathways or for therapeutic applications, analogs of
these compounds have been synthesized and phos-
phorylation reactions were developed. Among phos-
phorylating agents, phosphoric acid monoesters
((RO)P(O)(OH)2), phosphoric acid diesters ((HO)-
P(O)(OR)2), phosphorus pentoxide (P2O5), and phos-
phorus trichloride (PCl3) are commonly used.2 In the
more recent literature, H-phosphonate monoesters have
emerged as an interesting option to obtain phosphates in
an atom-economical way. Several examples of phospho-
lipid analogs,3 carbohydrate analogs,4 peptide analogs,5
and nucleotide analogs6 syntheses involved H-phospho-
nate monoesters intermediates.7
Our laboratory has been involved in the development of
phosphorus–carbon bond formation using inexpensive
and easily handled hypophosphorous acid (H3PO2)
and its derivatives.13 Based on the transfer hydrogena-
tion mechanism,14 we developed the hydrophosphinyl-
ation of alkenes and alkynes. We postulated that H3PO2
and its derivatives in the presence of a metal catalyst
undergo an equilibrium (Scheme 1) between the P(V) form
(2) and phosphinidene oxide complex (3) and we showed
this equilibrium can be controlled by using different
phosphine ligands. Based on this mechanism, we found
a new atom-economical, efficient, and catalytic way to
prepare H-phosphonate monoesters (1) by trapping
phosphinidene oxide (3) with an alcohol.
O
H
HO
P
H
2
oxidative
addition
Current methods to access H-phosphonate monoesters
(1) can be organized into two groups. The first uses
Pd(0)Ln
HO
8
H
O
P
P(III) phosphorus compounds such as PCl3 or salicyl-
O
P
PdLnH
OH
PdLnH
H
chlorophosphite9 in the presence of an alcohol and a
base such as tetrazole or imidazole. The second group
PdLn
H
HO
P
HO
3
10
uses P(V) phosphorus compounds such as H3PO3
Transfer
hydrogenation
Hydrophosphinylation
or
ROH
and diphenyl-H-phosphonate11 in the presence of an
alcohol, or the hydrolysis of H-phosphonate diesters.12
O
O
P
OR
H
HO
H
HO
P
1
*
Scheme 1. Hydrophosphinylation and transfer hydrogenation mecha-
Corresponding author. Tel.: +1 817 257 6201; fax: +1 817 257
nisms.
5951; e-mail: j.montchamp@tcu.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.057

6506
L. Coudray et al. / Tetrahedron Letters 48 (2007) 6505–6508
Table 1. Optimization of the catalytic oxidative phosphorylation of menthola
Entry
H3PO2 (equiv)b
Catalyst
Solventc
Toluene
Yieldd (%)
Type
—
Amount (mol %)
—
1
3.0
0e
2a
2b
2c
1.5
1.5
1.3
Ni on Al2O3/SiO2
Ni on Al2O3/SiO2
Ni on Al2O3/SiO2
5
5
5
Toluene/CH3CN (1/1)
Toluene
Toluene
13
85
61
3a
3b
3c
3d
1.5
1.5
1.5
1.5
Pd/C
Pd/C
Pd/C
Pd/C
5
5
5
5
Toluene/CH3CN (1/1)
Toluene
CH3CN
88
70
74
49
DMF
4a
4b
4c
1.2
1.0
3.0
Pd/C
Pd/C
Pd/C
5
5
5
Toluene/CH3CN (1/1)
Toluene/CH3CN (1/1)
Toluene/CH3CN (1/1)
77
62
80
5a
5b
5c
1.5
1.5
1.5
Pd/C
Pd/C
Pd/C
3
2
1
Toluene/CH3CN (1/1)
Toluene/CH3CN (1/1)
Toluene/CH3CN (1/1)
80
76
63
a Unless otherwise noted, reactions were conducted with 1.0 equiv of menthol (0.32 M in solvent), 5 mol % catalyst under N2 at 85 ꢁC for 24 h.
b Commercial 50 wt % aqueous H3PO2 was concentrated in vacuo (0.5 mmHg) for 30 min at rt.
c
˚
Toluene and CH3CN were freshly distilled over CaH2, and DMF was stored over 4 A sieves before use.
d H-Menthyl phosphonate was isolated by extraction of the acid form.
e Unreacted H3PO2 only.
Menthol was selected as test substrate to investigate the
different parameters of the reaction: catalyst, solvent,
temperature, and stoichiometry (Table 1).15 H-Menthyl
phosphonate was isolated by a basic–acidic extractive
work-up to afford the acid form. First, and as expected,
no product is formed in the absence of a catalyst (entry
1). Although the desired reaction takes place in all other
cases, significant differences are observed. Since we were
looking for an inexpensive catalytic P–O bond forma-
tion, Pd/C and Ni/Al2O3–SiO2 were selected as cata-
lysts. These catalysts proceed differently depending on
the solvents (entries 2a–c vs 3a–d). Although the best
Table 2. Scope of the catalytic oxidative phosphorylation
Entrya
Alcohol
H-Phosphonate
Isolated yieldb (%)
88
1
(À)-Menthol
OPO2H2
2
3
Borneol
70
97
OPO2H2
OPO2H2
(+)-Fenchyl Alcohol
4
5
3,3-Dimethyl-butan-2-ol
2,4-Dimethyl-pentan-3-ol
69
78
OPO2H2
OPO2H2
O
6
Pregnenolone
67
H
H
H2O2PO

L. Coudray et al. / Tetrahedron Letters 48 (2007) 6505–6508
6507
Table 2 (continued)
Entrya
Alcohol
H-Phosphonate
Isolated yieldb (%)
67
7
3-Phenyl-propan-1-ol
OPO2H2
OPO2H2
OBn
8
9
Dibenzyl glycerol
Dec-5-yn-1-ol
68
80
OBn
OPO2H2
3
2
10
11
3-Chloro-1-propanol
3-Bromo-1-propanol
Cl
OPO2H2
49c
37c
Br
OPO2H2
OPO2H2
12
Benzyl alcohol
56c
a See Supplementary data for detailed experimental procedures. Unless otherwise noted, reactions were conducted with 1.0 equiv of alcohol (0.32 M),
1.5 equiv of concentrated H3PO2 (prepared by evaporation of a commercial aqueous solution in vacuo (0.5 mmHg), for 30 min at rt) and 5 mol %
Pd/C, in distilled toluene–CH3CN (1:1, v/v), under nitrogen, at 85 ꢁC for 24 h.
b Unless otherwise noted, the H-phosphonate is isolated by extraction as the acid form.
c H-Phosphonate was isolated by extraction and precipitation of the ammonium salt.
conditions are Pd/C in a toluene/CH3CN mixture (1:1,
v/v) (entry 3a), it should be noted that Ni/Al2O3–SiO2
in toluene (entry 2b) leads to the product in comparable
yield. Entries 3a and 4 show the influence of H3PO2 stoi-
chiometry. In this process, residual water competes with
the alcohol for 3 thereby transforming H3PO2 into
H3PO3. Therefore, decreasing the amount of H3PO2
leads to lower yields (entries 4a and b vs entries 3a
and 4c) and the optimum appears to be 1.5 equiv
(entries 2b and 3a). As expected, catalyst loading controls
the rate of the reaction. With Pd at 1 mol % loading in
Pd/C, the reaction still proceeds in 63% yield after
24 h (entry 5c). On the other hand, reaction temperature
is a critical parameter, and influences dramatically the
speed of the reaction. Reactions performed at room tem-
perature and at 40 ꢁC, led to only 4% and 6% yields,
respectively.
7–12 and 1–6, respectively). But in spite of various ef-
forts, the products derived from tertiary alcohols could
not be isolated. As Cherbuliez et al. reported, it appears
that these products are unstable in acidic conditions and
elimination takes place.17
Hindered substrates give as good a yield as the unhin-
dered alcohols (entries 3–5), thus supporting a highly
reactive phosphinidene oxide intermediate. It should
be noted that various functionalities, such as ketone
(entry 6), alkene (entry 6), alkyne (entry 9), and halides
(entries 10 and 11) are tolerated.
In conclusion, a simple and catalytic phosphorus–oxy-
gen bond forming-reaction was developed based on the
postulated transfer hydrogenation mechanism. Various
primary and secondary alcohols, including hindered
compounds, reacted satisfactorily. Hypophosphorous
acid was shown to be a useful and inexpensive reagent
to prepare various H-phosphonate monoesters via an
oxidative phosphorylation which likely involves a highly
reactive phosphinidene oxide intermediate. The method
is atom-economical as it does not rely on protecting
group strategies or on phosphorus(III) chlorides.
Reactivities of different H3PO2 salts (NH3, PhNH2,
Et3N, Na) were also tested but unsuccessfully (the
sodium salt gave a 5% yield in CH3CN or DMF). Dorf-
man and Aleshkova have studied the reaction of
NaH2PO2 with methanol or butanol catalyzed by
PdCl2.16 The alcohols were employed as solvents and
no yields were reported.
Acknowledgement
After the establishment of the best conditions for men-
thol, we investigated the scope of the reaction (Table
2).15 In most cases, the H-phosphonate monoester can
be isolated in its acid form, in moderate to good yield
by a basic–acidic extractive work-up (entries 1–9). In
the case of more water-soluble products (entries 10–
12), a simple extractive work-up followed by precipita-
tion of the ammonium salt was necessary. Primary and
secondary alcohols react well in this reaction (entries
We gratefully acknowledge the National Institute of
General Medical Sciences/NIH (1R01 GM067610) for
the financial support of this research.
Supplementary data
Representative experimental procedures and spectro-
scopic data. This material. Supplementary data associ-

6508
L. Coudray et al. / Tetrahedron Letters 48 (2007) 6505–6508
27, 2661–2664; (b) Knerr, L.; Pannecoucke, X.; Schmitt,
G.; Luu, B. Tetrahedron Lett. 1996, 37, 5123–5126; (c)
Lartia, R.; Asseline, U. Tetrahedron Lett. 2004, 45, 5949–
5952.
ated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2007.07.057.
References and notes
10. (a) Cherbuliez, E.; Hunkeler, F.; Weber, G.; Rabinowitz,
J. Helv. Chim. Acta 1964, 47, 1647–1653; (b) Nifant’ev,
E. E.; Kil’disheva, V. R.; Nasonovskii, I. S. J. Appl. Chem.
U.S.S.R. 1969, 42, 2443–2446.
11. (a) Jankowska, J.; Sobkowski, M.; Stawinski, J.; Kra-
szewski, A. Tetrahedron Lett. 1994, 35, 3355–3358; (b)
Kers, A.; Kers, I.; Stawinski, J.; Sobkowski, M.; Kra-
szewski, A. Synthesis 1995, 4, 427–430.
1. For examples of different reactions involving H-phospho-
nate monoesters as starting material, see: (a) Laskorin, B.
N.; Yakshin, V. V.; Bulgakova, V. B. J. Gen. Chem.
U.S.S.R. 1976, 46, 2372–2376; (b) Iyer, V. V.; Griesgraber,
G. W.; Radmer, M. R.; McIntee, E. J.; Wagner, C. R.
J. Med. Chem. 2000, 43, 2266–2274; (c) Chang, S.-L.;
Griesgraber, G.; Wagner, C. R. Nucleosides Nucleotides
2001, 20, 1571–1582; (d) Michalski, J.; Modro, T.;
Zwierzak, A. J. Chem. Soc. 1961, 4904–4906.
12. Hammond, P. J. Chem. Soc. 1962, 2521–2522.
13. (a) Montchamp, J.-L.; Dumond, Y. R. J. Am. Chem. Soc.
2001, 123, 510–511; (b) Dumond, Y. R.; Montchamp,
`
J.-L. Organomet. Chem. 2002, 653, 252–260; (c) Deprele,
2. Slotin, L. A. Synthesis 1977, 737–752.
S.; Montchamp, J.-L. J. Am. Chem. Soc. 2002, 124, 9386–
3. For examples of phospholipids analogs synthesis via H-
phosphonates: (a) Lindh, I.; Stawinski, J. J. Org. Chem.
`
9387; (d) Deprele, S.; Montchamp, J.-L. Org. Lett. 2004,
`
´
6, 3805–3808; (e) Ribiere, P.; Bravo-Altamirano, K.;
1989, 54, 1338–1342; (b) Garcıa, M. L.; Pascual, J.;
`
´
Antczak, M. I.; Hawkins, J. D.; Montchamp, J.-L. J.
Org. Chem. 2005, 70, 4064–4072; For a review see: (f)
Montchamp, J.-L. J. Organomet. Chem. 2005, 690, 2388–
2406.
Borras, L.; Andreu, J. A.; Fos, E.; Mauleon, D.; Carga-
nico, G.; Arcamone, F. Tetrahedron 1991, 47, 10023–
10034.
4. For examples of carbohydrate analogs synthesis via H-
phosphonates: (a) Garegg, P. J.; Hansson, J.; Helland,
A.-C.; Oscarson, S. Tetrahedron Lett. 1999, 40, 3049–3052;
(b) Yashunsky, D. V.; Nikolaev, A. V. J. Chem. Soc.,
Perkin Trans.1 2000, 8, 1195–1198.
14. Reviews: (a) Brieger, G.; Nestrick, T. J. Chem. Rev. 1974,
74, 567–580; (b) Johnstone, R. A. W.; Wilby, A. H.;
Entwistle, A. I. Chem. Rev. 1985, 85, 129–170; Examples:
(c) Boyer, S. K.; Bach, J.; McKenna, J.; Jagdmann, E., Jr.
J. Org. Chem. 1985, 50, 3408–3411; (d) Khai, B. T.;
Arcelli, A. J. Org. Chem. 1989, 54, 949–953; (e) Brigas, A.
F.; Johnstone, R. A. W. Tetrahedron 1992, 48, 7735–7746.
15. General procedure: Aqueous hypophosphorous acid
(50 wt %) was concentrated in vacuo (0.5 mmHg) for
30 min at rt. H3PO2 (1.5 equiv, 4.8 mmol), alcohol
(1.0 equiv, 3.2 mmol), Pd/C (10 wt %, 5 mol % Pd,
0.16 mmol) in a mixture of distilled toluene–acetonitrile
(10 mL, 1:1 v/v) were heated at 85 ꢁC under a nitrogen
atmosphere for 24 h. After cooling, the reaction was
filtered through Celiteꢂ and concentrated in vacuo. The
resulting oil was dissolved in ethyl acetate (25 mL) and
washed with brine (10 mL, 3·). The organic layer was
extracted with NaHCO3 (0.5 M, 10 mL, 1·), then water
(10 mL, 2·). The combined aqueous layers were acidified
with 10% aqueous HCl until pH 1, and extracted with
ethyl acetate (25 mL, 3·). The combined organic layers
were washed with brine (5 mL, 1·), dried over MgSO4,
and concentration in vacuo to afford the acid form of H-
phosphonate monoesters.
5. For examples of peptide analogs synthesis via H-phos-
phonates: (a) Larsson, E.; Luning, B. Tetrahedron Lett.
¨
1994, 35, 2737–2738; (b) Hu, Y. J.; Rajagopalan, P. T.;
Pei, D. Bioorg. Med. Chem. Lett. 1998, 8, 2479–2482.
6. For examples of nucleotide analogs synthesis via H-
phosphonates: (a) Stawinski, J.; Stro¨mberg, R. Trends
Org. Chem. 1993, 4, 31–67; (b) Whalen, L. J.; McEvoy, K.
A.; Halcomb, R. L. Bioorg. Med. Chem. Lett. 2003, 13,
301–304; (c) Ludwig, P. S.; Schwendener, R. A.; Schott, H.
Eur. J. Med. Chem. 2005, 40, 494–504; (d) Yan, Z.; Kern,
E. R.; Gullen, E.; Cheng, Y.-C.; Drach, J. C.; Zemlicka, J.
J. Med. Chem. 2005, 48, 91–99; (e) Puech, F.; Gosselin, G.;
Balzarini, J.; De Clercq, E.; Imbach, J.-L. J. Med. Chem.
1988, 31, 1897–1907.
7. (a) Stawinski, J. In Handbook of Organophosphorus
Chemistry; Engel, R., Ed.; Marcel Dekker: New York,
1992; pp 377–434; (b) Stawinski, J.; Kraszewski, A. Acc.
Chem. Res. 2002, 35, 952–960.
8. (a) Boyd, D. R. J. Chem. Soc. 1901, 79, 1221–1227; (b)
Garegg, P. J.; Regberg, T.; Stawinski, J.; Stro¨mberg, R.
Chem. Scr. 1986, 26, 59–62; (c) Froehler, B. C.; Ng, P. G.;
Matteucci, M. D. Nucleic Acids Res. 1986, 14, 5399–5407.
9. (a) Marugg, J. E.; Tromp, M.; Kuyl-Yeheskiesly, E.; van
der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 1986,
16. Dorfman, Y. A.; Aleshkova, M. M. Kinet. Catal. 1998, 39,
852–858.
17. Cherbuliez, E.; Prince, R.; Rabinowitz, J. Helv. Chim.
Acta 1964, 47, 1653–1659.