A new entry to β-hydroxyphosphonates: The SmI2-mediated reaction of diethyl iodomethylphosphonate with carbonyl compounds

Article abstract of DOI:10.1016/S0040-4039(02)01539-3

In the presence of samarium iodide α-halophosphonates react with aliphatic carbonyl compounds (aldehydes and ketones) to afford β-hydroxyphosphonates in fairly good yields under neutral and mild conditions. Lower yields are obtained with aromatic carbonyl compounds.

Full text of DOI:10.1016/S0040-4039(02)01539-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7255–7257
A new entry to b-hydroxyphosphonates: the SmI2-mediated
reaction of diethyl iodomethylphosphonate with carbonyl
compounds
Fulvia Orsini* and Alessandro Caselli
Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano, Via Venezian 21 20133 Milano, Italy
Received 23 July 2002; accepted 25 July 2002
Abstract—In the presence of samarium iodide a-halophosphonates react with aliphatic carbonyl compounds (aldehydes and
ketones) to afford b-hydroxyphosphonates in fairly good yields under neutral and mild conditions. Lower yields are obtained with
aromatic carbonyl compounds. © 2002 Elsevier Science Ltd. All rights reserved.
Over the past decades there has been an increasing
interest in lanthanides and their use in organic synthe-
sis.1 Of the low-valent lanthanides, samarium (usually
as samarium iodide) has found the most widespread
application in a variety of chemical transformations
and carbonꢀcarbon bond forming processes (radical
cyclization, pinacol coupling reactions, ketyl–olefin
coupling reactions, Reformatsky-type and aldol type
reactions, conjugate additions).2 Among them, the
Reformatsky reaction,3 historically involving an
organozinc species, is a quite convenient way to pro-
duce b-hydroxy esters, very useful functional building
blocks. To this concern SmI2 can efficiently and advan-
tageously substitute zinc metal, in particular in
intramolecular asymmetric Reformatsky reactions.4
fluoride).8 They can also be prepared by addition of
dialkyl phosphites to aldehydes,9 reduction of b-
ketophosphonates,10 TiCl4-catalyzed opening of 1,3-
dioxane
acetals
with
trimethyl
phosphites.11
Ether-soluble Co(0) complexes have been used to syn-
thesise b-hydroxyphosphonates with advantages with
respect to previous procedures.12 More recently b-
hydroxyphosphonates were prepared via a three-com-
ponent coupling of acylphosphonate (from acyl
chloride and triethyl phosphite) and two carbonyl com-
pounds promoted by low-valent samarium (4 equiv.) in
tetrahydrofuran–hexamethylphosphoramide solution.13
The aim of present work was to investigate the
efficiency of samarium iodide in promoting reactions of
a-halophosphonates and carbonyl compounds (alde-
hydes, ketones) to produce b-hydroxyphosphonates.
The results are summarised in Table 1.
b-Hydroxy alkane phosphonates are also highly valu-
able compounds, due to their potential biological activ-
ities as stable biomimetics of the corresponding
phosphates and to their ability to mimic their car-
boxylic counterparts. Moreover, they also serve as pre-
cursors for a variety of substituted phosphonates.
Unfortunately, zinc does not efficiently promote the
reaction between a-halophosphonates and carbonyl
compounds to produce b-hydroxyphosphonates,5 that
are commonly prepared by reaction of a-metallated
phosphonates (from a-lithiation of phosphonates6 with
lithium alkyls at low temperatures) with carbonyls7 or
epoxides (the latter in the presence of boron tri-
To investigate the ability of SmI2 to promote these
Reformatsky-type reactions, different experiments were
performed using diethyl iodomethylphosphonate as a
model for a-halophosphonate.
The best results have been obtained by the simulta-
neous addition of the organic reagents to a 0.1 M
solution of SmI2 (2.2 molar equivalents) in tetra-
hydrofuran. Although the mechanism of the above
reaction has not been studied, the requirement of at
least two molar equivalents of samarium iodide would
suggest initial formation of a radical species and its
further reduction to an organosamarium species by the
second equivalent of samarium iodide.
Keywords: b-hydroxyphosphonates; samarium iodide.
* Corresponding author. Tel.: +39-02-50314111/4108; fax: +39-02-
50314106; e-mail: fulvia.orsini@unimi.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01539-3

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F. Orsini, A. Caselli / Tetrahedron Letters 43 (2002) 7255–7257
Table 1. Reactions between diethyl iodomethylphosphonate and aldehydes and ketonesa
The reactions proceeded in good yields for aliphatic
aldehydes (79–89%) and ketones such as cyclohexanone
(99%), albeit in the latter introduction of a ketal func-
tion dramatically lowered the yields (entry 5).† Lower
yields were also obtained with an easily enolizable
ketone such as b-tetralone. Benzaldehyde and acetophe-
none, chosen as models for aromatic carbonyl com-
pounds (that are more easily reduced to pinacols by
samarium iodide than their aliphatic counterparts),14
gave indeed modest yields of b-hydroxyphosphonate
(35–45%), accompanied by the product formed by
water elimination from the hydroxylic function. In
these cases (entries 7 and 8) appreciable recovery of the
corresponding pinacol (24–25%) and diethyl methane
phosphonate (23–39%) was also observed. Aromatic
a,b-unsaturated aldehydes such as cinnamaldehyde
gave mixtures of many unidentified products (not
reported in Table 1).
For one model system (diethyl iodomethylphosphonate
and benzaldehyde) the reaction was also carried out
using different ratios of organic reagents/samarium
iodide (1/1; 1/2; 1/2.5); different orders of addition of
the organic reagents to samarium iodide; and adding a
co-solvent (DMF or DMPU). The results confirmed the
requirement of 2 equivalents of samarium iodide: addi-
tion of diethyl iodomethylphosphonate to an equimolar
amount of samarium iodide, followed by the carbonyl
compound (about 10 min later) resulted in the produc-
† Although no experimental evidence has been searched, hydrolysis of
the ketal function followed by reaction of the resulting 1,4-cyclo-
hexanedione to afford a water-soluble diphosphonate can be con-
sidered: the yield of the crude reaction mixture recovered from
water was poor, and the monophosphonate obtained in the reaction
is sparingly soluble in water.

F. Orsini, A. Caselli / Tetrahedron Letters 43 (2002) 7255–7257
Press: London, 1994.
7257
tion ofdiethyl methane phosphonate (50%) andunreacted
diethyl iodomethylphosphonate (50%), whereas the addi-
tion compound was not observed. Addition of diethyl
iodomethylphosphonate to 2 equivalents of samarium
iodide, followed by the carbonyl compound (about 10
min. later) gave comparable total yields (of addition and
dehydration products) with respect to the simultaneous
addition of the organic reagents. Addition of co-solvents
did not improve the reaction.
2. (a) Steel, P. J. Chem. Soc., Perkin Trans. 1 2001, 2727–
2751; (b) Krief, A.; Laval, A. M. Chem. Rev. 1999, 99,
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Menon Ed., Research Trends Pub., Trivandrum, India,
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In summary, the method outlined for the synthesis of
b-hydroxyphosphonates represents
a
convenient
approach with some advantages to known procedures:
high yields (for aliphatic compounds), mild and neutral
conditions (with no requirement of acid or base and
anhydrous freshly distilled solvents) and easy work-up of
the reaction and recovery of the products.
4. (a) Jacobsen, M. F.; Turks, M.; Hazell, R.; Skrydstrup,
T. J. Org. Chem. 2002, 67, 2411–2417; (b) Molander, G.
A.; Etter, J. B. J. Am. Chem. Soc. 1987, 109, 6556–6558.
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3725–3728.
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Lett. 1985, 26, 783–786; (b) Teulade, M. P.; Savignac, P.;
Aboujaoude, E. E.; Collignon, N. J. Organomet. Chem.
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Typical procedure. In a typical procedure, a THF solution
(2 mL) of diethyl iodomethylphosphonate (0.5 mmol) and
carbonyl compound (0.5 mmol) was added dropwise over
a 10 min period at room temperature to a stirred solution
of SmI2 in tetrahydrofuran (0.1 M, 12 mL). Soon after
the addition, the original blue solution turned to a yellow
suspension. The reaction was monitored by TLC (EtOAc/
n-hexane). The reaction mixture was treated with aqueous
HCl (0.1N solution, 3 mL) and extracted with ethyl
acetate (3×4 mL); the organic layer was washed with a
saturated Na2SO3 aqueous solution (2 mL), dried with
sodium sulfate, filtered, the solvent evaporated and the
crude purified by column chromatography.
9. (a) Devitt, P. G.; Kee, T. P. Tetrahedron 1995, 51,
10987–10996; (b) Blazis, V. J.; Kobbler, K. J.; Spilling, S.
J. Org. Chem. 1995, 60, 931–940.
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Acknowledgements
11. Yokomatsu, T.; Shibuya, S. Tetrahedron: Asymmetry
The National Research Council (C.N.R.) and Ministero
della Ricerca Scientifica e Tecnologica (MURST) are
thanked for financial support.
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K.; Makioka, Y.; Taniguchi, Y.; Fujiwara, Y. J. Org.
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