Convenient method for the preparation of heterodialkyl-H-phosphonates from diphenyl-H-phosphonate

Article abstract of DOI:10.1080/00397910801982282

A procedure for the introduction of two different alkyl chains (myristyl, oleyl and phytanyl) leading to heterodialkyl-H-phosphonates is reported, based on two successive transesterification reactions of commercially available diphenyl-H-phosphonate with the corresponding alcohols. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801982282

Synthetic Communicationsw, 38: 1688–1693, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801982282
Convenient Method for the Preparation of
Heterodialkyl-H-phosphonates from
Diphenyl-H-phosphonate
1
Angelique Durand Dal-Maso, Frederic Legendre,
1
´
´ ´
Casimir Blonski,2 and Pascal Hoffmann2
1Laboratoire de Recherche CAYLA-InVivoGen, Toulouse, France
2
´
LSPCMIB-UMR/CNRS 5068, Universite Paul Sabatier,
Toulouse, France
Abstract: A procedure for the introduction of two different alkyl chains (myristyl,
oleyl and phytanyl) leading to heterodialkyl-H-phosphonates is reported, based on
two successive transesterification reactions of commercially available diphenyl-H-
phosphonate with the corresponding alcohols.
Keywords: Alkyl chain, H-phosphonate, phosphite, phosphono lipids
INTRODUCTION
As H-phosphonate derivatives exist in solution as an equilibrium mixture of
two tautomeric forms (i.e., a tetracoordinate phosphonate form and a tricoor-
dinated phosphite form), these compounds behave similarly to phosphates
and at the same time preserve characteristic features and reactivity of phos-
phites.[1] Consequently, H-phosphonate chemistry constitute an alternative
to well-established methods based on phosphate [P(V)] and phosphite
[P(III)] derivatives for the preparation of phosphorus-containing compounds,
such as nucleotides or carbohydrates. Although several synthetic methods
for the preparation of H-phosphonate derivatives bearing two identical alkyl
chains (“homodialkyl-H-phosphonates”) have been developed, such as direct
Received in Poland October 25, 2007
Address correspondence to Pascal Hoffmann, LSPCMIB-UMR/CNRS 5068,
´
Universite Paul Sabatier, 31062, Toulouse, cedex 9, France. E-mail: hoffmann@cict.fr
1688

Heterodialkyl-H-phosphonates
1689
esterification of phosphorus trichloride by the corresponding alcohol in the
absence of solvent,[2] or by transesterification of commercial diphenyl-H-
phosphonate (often miscalled diphenyl-phosphite) with an excess of the corre-
sponding alcohol[3] (Scheme 1), there remains a need for a straightforward and
general methodology toward the unsymmetrical introduction of two different
alkyl chains under mild conditions, leading to “heterodialkyl-H-phosphonates.”
Indeed, in the past decade, a number of phosphonate-derived amphiphiles
resembling the natural phosphonolipids of cell membranes that displayed
some interesting features as nonviral vectors for gene delivery[4] were
described. However, although phosphonolipids bearing two identical alkyl
chains of various natures have been investigated as gene delivery
vectors,[3,5–7] no attention has been paid to phosphonolipids possessing two
different alkyl chains. In this work, we report a convenient procedure for
the preparation of heterodialkyl-H-phosphonates that could serve as precur-
sors for the preparation of such heterophosphonolipids. The method is based
on two successive transesterification reactions of commercially available
diphenyl-H-phosphonate (Scheme 2). As lipid chains, C14-saturated
(myristyl), C18-unsaturated (oleyl), and phytanyl moities were chosen.
RESULTS AND DISCUSSION
As expected, simultaneous or successive addition of the two alcohol chains to
a solution of diphenyl-H-phosphonate in the presence of pyridine resulted in a
mixture of both homodimeric and heterodimeric H-phosphonates, as revealed
by 31P NMR, which were not separable by distillation or common chromato-
graphic methods. Therefore, we developed a simple procedure for the
unsymmetrical introduction of two different alkyl chains leading to hetero-
dialkylphosphites, based on two successive transesterification reactions of
commercially available diphenylphosphite.
Synthesis of Phenylalkyl-H-phosphonates (2) from Diphenyl-H-
phosphonate (Scheme 2, Table 1)
By examining a variety of reaction conditions, we found that the process was
most efficient at room temperature in the absence of solvent, with 1 equivalent
Scheme 1. Preparation of homodialkyl-H-phosphonates from (a) phosphorus trichlo-
ride[2] and (b) diphenylphosphite[3] in the presence of the corresponding alcohol
(R-OH).

1690
A. D. Dal-Maso et al.
Scheme 2. Synthesis of heterodialkyl-H-phosphonates. Reagents and conditions: i,
pyridine (0.8 eq.), R1OH (0.8 eq.), 2 h; ii, pyridine (0.8 eq.), R2OH (0.8 eq.), 3 h.
of diphenylphosphite, 0.8 equivalent of pyridine, and 0.8 equivalent of the
corresponding alcohol (tetradecanol and phytanol, R1OH, 0.8 equivalent).
The reactions could be followed by 31P NMR spectroscopy, observing the
conversion of diphenylphosphite to the mono-alkylated H-phosphonate
compound. The reactions were completed in 2 h, and no further significant
changes in the NMR spectra could be observed. In these experimental con-
ditions, the expected monoalkylated-H-phosphonates 2a and 2b were
obtained with good yields (90 and 82%, respectively) and could be easily
isolated by simple removal of the formed phenol and the excess of
diphenyl-H-phosphonate by distillation.
Synthesis of Dialkyl-H-phosphonates (3) from Phenylalkyl-H-
phosphonate (Scheme 2, Table 1)
The introduction of the second alkyl chain was achieved by mixing the phe-
nylalkyl-H-phosphonate intermediate (2) to 0.8 equivalent of the corre-
sponding alcohol (R2OH) and pyridine (0.8 equiv.) at room temperature.
The reactions were followed by changes in the 31P NMR spectra, which
showed a shift toward to more positive values of the phosphonate peak,
indicating the introduction of the second alkyl chain. After distillation
under reduced pressure to remove phenol and pyridine, H-phosphonate
Table 1. Mono- (2) and di- (3) alkyl-H-phosphonates produced via Scheme 2
Compound
R1
R2
Yield (%)
31P NMR d (ppm)
2a
2b
3a
3b
3c
C14H29
C20H41
C14H29
C20H41
C20H41
—
—
90
82
80
72
75
4.8
4.7
8
C18H35
C14H29
C18H35
7.9
7.9

Heterodialkyl-H-phosphonates
1691
compounds 3 were obtained with yields in the 70–80% range. All
compounds were then characterized by mass spectrometry and in solution
by multinuclear NMR data.
In conclusion, a convenient and high-yielding route to heterodialkyl-
H-phosphonates bearing two different alkyl chains has been developed
using diphenyl-H-phosphonate as starting material. Compounds 3 were
then successfully used as precursors for the synthesis of a series of
pyridinium-based phosphonolipids that were evaluated as transfection
agents.[8]
EXPERIMENTAL
All chemicals were obtained from Aldrich or Acros Organics and used without
further purification. Nuclear magnetic resonance spectra were recorded on a
Bruker AC 300 spectrometer (1H and 13C NMR) or on a Bruker AC 200 spec-
trometer (31P NMR), and mass spectra were measured on a Nermag R10-10C
mass spectrometer.
Phenyltetradecyl-H-phosphonate (2a)
Tetradecanol (0.9 g, 4.7 mmol) and anhydrous pyridine (0.37 g, 4.7 mmol)
were added dropwise under argon to diphenylphosphite (1 mL, 5.3 mmol).
After 2 h at room temperature under magnetic stirring, the excess of diphenyl-
phosphite and phenol were removed by distillation (60 8C, 1 mm Hg) to obtain
1
1.3 g of 2a as a white solid (yield: 90%). H NMR (300 MHz, CDCl3) d
3
(ppm): 0.87 (t, 3H, JH-H ¼ 6.6 Hz, H-14), 1.20–1.45 (m, 22H, H-3–H-13),
3
1.60–1.70 (m, 2H, H-2), 4.01 (q, 2H, JH-H ¼ 3JH-P ¼ 6.8 Hz, CH2-O), 7.08
1
(d, 1H, JH-P ¼ 716.4 Hz, P-H), 7.10–7.20 (m, 3H, Harom), 7.28–7.36
(m, 2H, Harom). 31P NMR (81 MHz, CDCl3) d (ppm): 4.8. MS (DCI/NH3),
m/z: 355 (MHþ).
Phenylphytanyl-H-phosphonate (2b)
This compound was obtained as a colorless oil from diphenylphosphite
(5.3 mmol) and phytanol (4.2 mmol) by the same procedure used for the prep-
1
aration of compound 2a. Yield: 82% (1.5 g). H NMR (300 MHz, CDCl3) d
3
(ppm): 0.81–0.89 (m, 12H, CH3), 0.90 (d, 3H, JH-H ¼ 6.1 Hz, CH3), 0.98–
3
1.78 (m, 24H, H-2–H-15), 4.11 (q, 2H, JH-H ¼ 3JH-P ¼ 6.8 Hz, CH2-O),
1
7.07 (d, 1H, JH-P ¼ 716.5 Hz, P-H), 7.10–7.20 (m, 3H, Harom), 7.28–7.36
(m, 2H, Harom). 31P NMR (81 MHz, CDCl3) d (ppm): 4.7. MS (ES) m/z:
439 (MHþ).

1692
A. D. Dal-Maso et al.
Oleyltetradecyl-H-phosphonate (3a)
Pyridine (0.09 g, 1.12 mmol) and oleyl alcohol (cis-9-octadecen-1-ol, 0.30 g,
1.12 mmol) were added to 2a (0.50 g, 1.41 mmol), and the solution was stirred
for 3 h at room temperature. Pyridine (under reduced pressure) and phenol
(distillated at 60 8C, 1 mm Hg) were then removed to afford 0.47 g (yield:
1
80%) of 3a (white solid). H NMR (300 MHz, CDCl3) d (ppm): 0.87 (t, 6H,
3JH-H ¼ 6.6 Hz), 1.13–1.45 (m, 44H), 1.52–1.74 (m, 4H), 1.89–2.08
(m, 8H), 5.29–5.43 (m, 4H), 3.99–4.26 (m, 2H, CH2-O), 6.81 (d, 1H,
1JH-P ¼ 696.1 Hz, P-H). 13C NMR (75 MHz, CDCl3) d (ppm; oleyl chain,
C-n; myristyl chain, C-n0): 14.1 (C-18, C-140), 22.6 (C-17, C-130), 25.5
(C-3, C-30), 27.2 (C-8, C11), 29.1–29.6 (C-4–C-7, C-12–C-15, C-40 –
3
C-110), 30.6 (d, JC-P ¼ 6.4 Hz, C-2, C-20), 31.8 (C-16, C-120), 66.2
2
(d, JC-P ¼ 6.8 Hz, C-1, C-10), 129.8 and 129.9 (C-9, C-10). 31P NMR
(81 MHz, CDCl3) d (ppm): 8.0. MS (ES) m/z: 529 (MHþ), 551 (MNaþ).
Phytanyltetradecyl-H-phosphonate (3b)
This compound was obtained as a colorless oil from 2b (0.50 g) and 1-tetra-
decanol (0.19 g) by the same procedure used for the preparation of
1
compound 3a. Yield: 72% (0.36 g). H NMR (300 MHz, CDCl3) d (ppm):
3
0.80–0.87 (m, 24H), 0.90 (d, 3H, JH-H ¼ 6.1 Hz, CH3), 0.98–1.78
1
(m, 48H), 4.11–4.32 (m, 4H, CH2-O), 6.82 (d, JH-P ¼ 695.2 Hz, P-H). 13C
NMR (75 MHz, CDCl3) d (ppm; phytanyl chain, C-n; myristyl chain, C-n0):
14.0 (C-140), 19.5 and 19.7 (3 ꢀ CH3), 22.6 and 22.7 (2 ꢀ CH3), 22.8 (C-
130), 24.4, 24.5, and 24.8 (C-5, C-9, C-13), 26.1 (C-30), 28.0 (C-15), 29.1–
3
29.6 (C-40 –C-110, C-3), 30.6 (d, JC-P ¼ 6.4 Hz, C-20), 31.8 (C-120), 31.9
(C-160), 32.8 (C-7, C-11), 37.0–37.8 (C-2, C-4, C-6, C-8, C-10, C-12), 39.4
2
2
(C-14), 65.4 (d, JC-P ¼ 6.7 Hz, C-1), 66.0 (d, JC-P ¼ 6.0 Hz, C-10).
31P NMR (81 MHz, CDCl3 d (ppm): 7.9. MS (ES) m/z: 559 (MHþ).
Oleylphytanyl-H-phosphonate (3c)
This compound was obtained as a colorless oil from 2b (0.50 g) and oleyl
alcohol (0.25 mL) by the same procedure used for the preparation of
1
compound 3a. Yield: 75% (0.51 g). H NMR (300 MHz, CDCl3) d (ppm):
3
0.80–0.87 (m, 15H), 0.90 (d, 3H, JH-H ¼ 6.1 Hz, CH3), 1.00–1.77
(m, 48H), 1.89–2.08 (m, 4H), 4.11–4.32 (m, 4H, CH2-O), 5.29–5.43
1
(m, 4H), 6.82 (d, JH-P ¼ 696.2 Hz, P-H). 13C NMR (75 MHz, CDCl3) d
(ppm; phytanyl chain, C-n; oleyl chain, C-n0): 14.0 (C-180), 19.5 and 19.7
(CH3), 22.6, 22.7, and 22.8 (2 ꢀ CH3, C170), 24.4, 24.5, and 24.8 (C-5,
C-9, C-13), 25.6 (C-30), 27.2 (C-80, C-110), 28.0 (C-15), 29.1–29.6 (C-40 –
3
C-70, C-120 –C-150), 29.4 (C-3), 30.7 (d, JC-P ¼ 5.9 Hz, C-20), 31.9 (C-160),

Heterodialkyl-H-phosphonates
1693
32.8 (C-7, C-11), 37.0–37.8 (C-2, C-4, C-6, C-8, C-10, C-12), 39.5 (C-14),
2
2
65.4 (d, JC-P ¼ 6.7 Hz, C-1), 66.0 (d, JC-P ¼ 6.0 Hz, C-10), 129.8
and 129.9 (C-90, C-100). 31P NMR (81 MHz, CDCl3) d (ppm): 7.9. MS (ES)
m/z: 613 (MHþ).
ACKNOWLEDGMENT
´
Angelique Durand Dal-Maso was supported by the National Association for
Technical Research (ANRT, grant CIFRE).
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