A selective and mild synthetic route to dialkyl phosphates

Article abstract of DOI:10.1055/s-2003-38074

A very mild synthetic route to dialkyl phosphates is described. Reaction of the appropriate alcohol with PCl₃ followed by treatment with pyridine and CCl₄ afforded the corresponding trichloromethyl ester. Subsequent reaction with the triethylamine salt of acetic acid followed by hydrolysis of the formed mixed anhydride under very mild conditions afforded the dialkyl phosphates in high yield.

Full text of DOI:10.1055/s-2003-38074

PAPER
695
A Selective and Mild Synthetic Route to Dialkyl Phosphates
Synthesis
o
of
D
ialkyl Phosphate
s
anna M. Kuiper,a Ron Hulst,b Jan B. F. N. Engberts*a
a
Physical Organic Chemistry Unit, Stratingh Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
b
Kiadis B.V., Niels Bohrweg 11-13, 2333 CA Leiden, The Netherlands
Fax +31(50)3634296; E-mail: J.B.F.N.Engberts@chem.rug.nl
Received 28 October 2002; revised 27 January 2003
lead to severe problems.10 Also routes including oxidative
steps4,15 appeared unsuccessful for the preparation of
long-chain dialkyl phosphates and/or the synthesis of di-
alkyl phosphates with functionalized groups.
Abstract: A very mild synthetic route to dialkyl phosphates is de-
scribed. Reaction of the appropriate alcohol with PCl3 followed by
treatment with pyridine and CCl4 afforded the corresponding
trichloromethyl ester. Subsequent reaction with the triethylamine
salt of acetic acid followed by hydrolysis of the formed mixed an-
hydride under very mild conditions afforded the dialkyl phosphates
in high yield.
Driven by the need for a better synthetic protocol, we re-
port the synthesis of long- and/or functionalized-chain di-
alkyl phosphates via a new and very mild route.
Key words: dialkyl phosphates, lipids, alcohols, dialkyl phospho-
The first step of the procedure (Scheme 1) consists of an
Arbuzov reaction16 at room temperature using 3 equiva-
lents of the appropriate alcohol, 2 equivalents of pyridine
and PCl3,17 yielding dialkyl phosphonates 2 in 53–75%
isolated yield. The reaction proceeds smoothly and can be
monitored by TLC and 1H or 31P NMR (31P NMR δ = ca.
7.5 ppm). If necessary, additional aliquots of pyridine and
PCl3 were added in order to ensure complete consumption
of the alcohol, since traces of alcohol can cause purifica-
tion problems. The dialkyl phosphonates are stable and
can be purified by crystallization or column chromatogra-
phy. Subsequently, phosphonates 2 are treated with CCl4
and Et3N, under the Atherton–Openshaw–Todd condi-
tions,18 yielding quantitatively the trichloromethyl esters
3 (31P NMR δ = ca. –13 ppm), which were not isolated. A
catalytic amount of diisopropylethylamine may be added
to accelerate the reaction rate. After evaporation of the re-
agents, the trichloromethyl esters 3 were converted into
the mixed anhydrides 4 (31P NMR δ = ca. –1 ppm) by
treatment with acetic acid and Et3N.19,20 Mild acidic hy-
drolysis of the anhydrides 4 afforded dialkyl phosphates 5
(31P NMR δ = ca. 1 ppm) in 56–73% isolated yield.21
nates, azobenzene
Important aspects of the chemistry of biological cell mem-
branes can be successfully mimicked by using bilayer ves-
icles formed from synthetically available amphiphiles.
For this purpose, sodium dialkyl phosphates are, among
others, often used.1–3 A variety of methods have been de-
veloped for the preparation of dialkyl phosphates.4–7 Most
of these are multi-step syntheses, which are either difficult
to perform or involve oxidation steps combined with the
necessity of elevated temperatures, often excluding the
use of alcohols containing functional groups. A frequently
applied method is the stepwise preparation of the dialkyl
phosphate via the mono-alkyl phosphate from pyrophos-
phoric acid using tetramethylammonium hydroxide
(TMAH) as base.8,9 The application of this procedure for
the preparation of long-chain lipid phosphates, however,
appeared troublesome due to the long reaction times need-
ed and difficult isolation of the product from the reaction
mixtures.10 Another standard procedure employs the reac-
tion of exactly two equivalents of alcohol with POCl3, fol-
lowed by aggressive (basic) hydrolysis of the intermediate
phosphoroxychloride.3,11 Although this procedure allows
straightforward preparation of short-chain phosphates, the
use of longer chain alcohols leads to less selective bis-es-
terification and significant saponification during the hy-
drolysis of the phosphoroxychloride intermediate.
Moreover, isolation of the products from the crude reac-
tion mixtures appeared troublesome and includes prepar-
In summary, starting from a suitable alcohol a simple and
mild synthetic protocol has been developed to obtain long
and/or functionalized chained dialkyl phosphates. More-
over, no oxidative or basic hydrolytic steps are involved.
All reactions proceed with total conversion, except for the first step.
No work-up, isolation or purification procedures were required for
the intermediate compounds 3 and 4. 4-Butyl aniline was distilled
ative TLC11 or exceedingly long crystallization times to before use.
isolate e.g. dioleyl phosphate.12 In search for improved
phosphorylation methods, several routes were proposed
using ‘exotic’ reagent settings.5,13,14 A major drawback,
however, is the need for preparation of the reagents,
whereas the removal of the protecting groups can also
1H, 31P and 13C NMR spectra were recorded at 25 °C on a Varian
VXR-300 spectrometer operating at 300 MHz for 1H, at 75.43 MHz
for 13C, and on a Varian Gemini-200 spectrometer operating at 200
MHz for the 1H, at 80.96 MHz for the 31P and at 50.29 MHz for 13
C
channels. For compounds 2a, 2d, and 2e no exact mass could be de-
termined, but the parent peak was in accordance with the structure.
The residual 1H signals of the deuterated solvents were used as in-
ternal chemical shift standard. Melting points (uncorrected) were
recorded using a Kofler hot stage apparatus equipped with a micro-
scope. Oleic acid, 9-bromononan-1-ol, 4-butylaniline, 6-bromohex-
Synthesis 2003, No. 5, Print: 01 04 2003.
Art Id.1437-210X,E;2003,0,05,0695,0698,ftx,en;T11402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

696
J. M. Kuiper et al.
PAPER
NaOH (3.2 g, 0.08 mol) and Na2CO3 (14 g, 0.13 mol) in cold H2O
(200 mL) . The precipitate was filtered off and crystallized from ac-
etone.
Yield: 15.20 g (74%).
Mp 81 °C (lit.22 79–82 °C).
1H NMR (200 MHz, CDCl3): δ = 0.95 (t, J = 7.2 Hz, 3 H), 1.29–
1.47 (m, 2 H), 1.56–1.71 (m, 2 H), 2.66 (t, J = 7.6 Hz, 2 H), 6.62–
6.69 (m, 2 H), 7.24–7.28 (m, 2 H), 7.62–7.70 (m, 2 H).
13C NMR (50 MHz, CDCl3): δ = 14.3, 23.4, 34.9, 36.4, 120.2,
122.7, 126.5, 129.9, 143.7, 145.1, 152.9, 174.0.
5-{[4-(4-butylphenyl)azo]-phenoxy}-pentan-1-ol (1d)
An identical protocol as described for 1a was followed. Starting
from 4-n-butyl-4′-hydroxy-azobenzene and 5-bromopentan-1-ol,23
the product was isolated in a 57% yield (1.43 g). The resulting yel-
low solid material was purified by crystallization from hexane.
Mp 74–75 °C.
1H NMR (200 MHz, CDCl3): δ = 0.94 (t, J = 7.2 Hz, 3 H), 1.30–
1.47 (m, 2 H), 1.52–1.72 (m, 6 H), 1.79–1.93 (m, 2 H), 2.68 (t,
J = 7.7 Hz, 2 H), 3.70 (m, 2 H), 4.05 (t, J = 6.5 Hz, 2 H), 6.97–7.01
(m, 2 H), 7.28–7.32 (m, 2 H), 7.78–7.82 (m, 2 H), 7.87–7.91 (m, 2
H).
13C NMR (50 MHz, CDCl3): δ = 13.9, 22.3, 28.9, 32.4, 33.4, 35.5,
62.7, 68.1, 114.6, 122.5, 124.5, 129.0, 145.8, 146.9, 151.0, 161.3.
HRMS: m/z calcd for C21H29N2O2, 340.21506; found, 340.21408.
6-{[4-(4-butylphenyl)azo]-phenoxy}-hexan-1-ol (1e)
An identical protocol as described for 1a was followed. Starting
form 4-n-butyl-4′-hydroxy-azobenzene and 6-bromohexan-1-ol the
product was isolated in a 55% yield (3.07 g). The resulting yellow
solid material was purified by crystallization from hexane.
Scheme 1 Reagents: (i) PCl3, pyridine (ii) CCl4, Et3N (iii)
CH3CO2H, Et3N, i-Pr2NEt (iv) H+/H2O.
Mp 75–76 °C.
1H NMR (200 MHz, CDCl3): δ = 0.89 (t, J = 7.3 Hz, 3 H), 1.27–
1.64 (m, 10 H), 1.74–1.83 (m, 2 H), 2.63 (t, J = 7.7 Hz, 2 H), 3.59–
3.65 (m, 2 H), 3.99 (t, J = 6.4 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H),
7.25 (d, J = 8.1 Hz, 2 H), 7.75 (d, J = 8.4 Hz, 2 H), 7.84 (m, 2 H).
an-1-ol, diethyl phosphite and 4-phenyl-azophenol were obtained
from Aldrich.
13C NMR (50 MHz, CDCl3): δ = 13.9, 22.3, 25.5, 25.8, 29.1, 32.6,
33.4, 35.5, 62.8, 68.1, 114.6, 122.5, 124.5, 129.0, 145.7, 146.9,
151.0, 161.3.
9-[(4-Phenylazo)-phenoxy]-nonan-1-ol (1a)
To 4-phenylazophenol (4.00 g, 20.16 mmol) in acetone (150 mL)
was added 9-bromononan-1-ol (4.52 g, 20.16 mmol), K2CO3 (5.56
g, 40.32 mmol) and a catalytic amount of KI (0.3 g, 1.8 mmol). The
mixture was refluxed for 5 d. The acetone was removed by evapo-
ration under reduced pressure. CH2Cl2 (300 mL) was added and the
organic layer was washed with H2O (3 × 150 mL). The organic layer
was dried over Na2SO4, filtered and concentrated under reduced
pressure. The resulting yellow solid material was purified by crys-
tallization from EtOAc (ca. 120 mL) affording yellow crystals in
75% yield (5.14 g).
HRMS: m/z calcd for C22H30N2O2, 354.23071; found, 354.23061.
Di-{9-[(4-phenylazo)-phenoxy]-nonyl} Phosphonate (2a)
To 1a (1.5 g, 4.41 mmol) in anhyd CH2Cl2 (15 mL) under a nitrogen
atmosphere, pyridine (2.94 mmol, 238 µL, 232 mg) and PCl3 (1.47
mmol, 128 µL, 202 mg) were slowly added. The reaction was mon-
itored using TLC (Silica, Et2O) or 31P NMR and additional portions
of pyridine and PCl3 (ratio 2:1) were added until all alcohol had re-
acted. After completion, the mixture was washed with brine (2 × 25
mL), dried over Na2SO4 and concentrated under reduced pressure.
The resulting material was stirred overnight in hexane (ca. 30 mL)
yielding small crystals. The crystalline material was further purified
by crystallization from EtOH (2 × ). Pure yellow crystals were ob-
tained in 53% yield (0.57 g).
Mp 107–108 °C.
1H NMR (200 MHz, CDCl3): δ = 1.35–1.61 (m, 12 H), 1.75–1.86
(m, 2 H), 3.65 (t, J = 6.5 Hz, 2 H), 4.04 (t, J = 6.5 Hz, 2 H), 6.97–
7.04 (m, 2 H), 7.39–7.55 (m, 3 H), 7.85–7.96 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 25.7, 26.0, 29.1, 29.3, 29.3, 29.5,
32.7, 63.0, 68.3, 114.7, 122.5, 124.7, 129.0, 130.3, 146.8, 152.7,
161.6.
Mp 89–95 ºC.
1H NMR (300 MHz, CDCl3): δ = 1.30–1.42 (m, 10 H), 1.60–1.67
(m, 2 H), 1.71–1.81 (m, 2 H), 3.96–4.05 (m, 4 H), 6.76 (d, J = 6.92
Hz, 1 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.35–7.47 (m, 3 H), 7.81–7.91
(m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 25.5, 26.0, 29.0, 29.1, 29.2, 29.4,
30.4, 65.7, 68.2, 114.6, 122.5, 125.7, 129.0, 130.3, 146.8, 152.7,
161.6.
HRMS: m/z calcd for C21H28N2O2, 340.21506; found, 340.21440.
4-Butyl-4′-hydroxy-azobenzene22
4-Butylaniline (12 g, 0.08 mol) was dissolved in a mixture of H2O–
acetone (200 mL, 1:1) and concd. HCl (20 mL). To the cooled soln,
NaNO2 (5.6 g, 0.08 mol) in cold H2O (100 mL) was added. The soln
was allowed to stand for 20 min in an ice bath. The resulting diazo-
nium soln was added to a cold soln of phenol (7.6 g, 0.08 mol),
Synthesis 2003, No. 5, 695–698 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Dialkyl Phosphates
697
31P NMR (81 MHz, CDCl3): δ = 7.51 ppm.
MS (EI+): m/z = 742.
purified by crystallization from EtOH affording yellow crystals in
66% yield (0.206 g),
Mp 124–128 ºC.
Dioleyl Phosphonate (2b)24
1H NMR (200 MHz, CDCl3): δ = 1.21–1.61 (m, 20 H), 1.66–1.84
(m, 8 H), 3.99–4.08 (m, 8 H), 6.99 (d, J = 8.8 Hz, 4 H), 7.42–7.53
(m, 6 H), 7.87–7.95 (m, 8 H).
13C NMR (75 MHz, C6D6–CD3OD, 5:1; 65 °C): δ = 25.8, 26.3, 29.4,
29.5, 29.6, 29.7, 30.7, 67.6, 68.5, 115.2, 123.0, 125.2, 129.2, 130.5,
147.7, 153.6, 162.3.
An identical protocol as described for 2a was followed starting from
oleyl alcohol.25 The product was purified by means of column chro-
matography (Silica, hexane–Et2O, 1:1). Product 2b was obtained as
a viscous oil in 75% yield (5.43 g).
1H NMR (200 MHz, CDCl3): δ = 0.88 (t, J = 6.5 Hz, 6 H), 1.20–
1.45 (m, 44 H), 1.61–1.80 (m, 4 H), 1.95–2.10 (m, 8 H), 4.00–4.11
(m, 4 H), 5.20–5.41 (m, 4 H), 6.80 (d, J = 692 Hz, 1 H).
31P NMR (81 MHz, CDCl3): δ = 1.32 ppm.
13C NMR (50 MHz, CDCl3): δ = 14.1, 22.6, 25.5, 27.1, 27.2, 29.0,
29.1, 29.3, 29.4, 29.5, 29.7, 29.7, 30.3, 30.4, 31.9, 65.7, 129.7,
129.9.
Anal. Calcd for C42H55N4O6P (742.9): C, 67.90; H, 7.46; N, 7.54.
Found: C, 67.80; H, 7.56; N, 7.44.
Dioleyl Phosphate (5b)5
An identical protocol as described for 5a was followed starting from
2b yielding 5b that was purified according to literature procedures8
and obtained as an oil in a 70% yield (0.72 g).
1H NMR (200 MHz, CDCl3): δ = 0.88 (t, J = 6.2 Hz, 6 H), 1.20–
1.40 (m, 44 H), 1.61–1.75 (m, 4 H), 1.91–2.11 (m, 8 H), 4.01 (q,
J = 6.6 Hz, 4 H), 5.31–5.37 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 14.1, 22.7, 25.4, 27.2, 29.1, 29.2,
29.3, 29.5, 29.6, 29.7, 30.1, 30.2, 31.9, 32.6, 67.6, 129.7, 129.9.
31P NMR (81 MHz, CDCl3): δ = 1.23 ppm.
31P NMR (81 MHz, CDCl3): δ = 7.47 ppm.
Di-(5-{[4-(4-butylphenyl)azo]-phenoxy}-pentyl) Phosphonate
(2d)
An identical protocol as described for 2a was followed. The result-
ing yellow crystals were isolated in 64% yield (0.68 g).
Mp 85–86 °C.
1H NMR (200 MHz, CDCl3): δ = 0.94 (t, J = 7.2 Hz, 6 H), 1.28–
1.47 (m, 4 H), 1.56–1.71 (m, 8 H), 1.73–1.89 (m, 8 H), 2.68 (t,
J = 7.7 Hz, 4 H), 4.00–4.18 (m, 8 H), 6.84 (d, J = 694 Hz, 1 H),
6.94–7.01 (m, 4 H), 7.26–7.31 (m, 4 H), 7.78–7.82 (m, 4 H), 7.86–
7.93 (m, 4 H).
Anal. Calcd for C36H71O4P (598.93): C, 72.18; H, 11.96. Found: C,
72.10; H, 11.79.
13C NMR (50 MHz, CD3OD): δ = 14.3, 23.4, 29.8, 31.2, 34.8, 36.5,
67.1, 69.1, 115.7, 123.4, 125.5, 130.0, 147.0, 148.0, 152.1, 162.8.
Diethyl Phosphate (5c)26
A similar method was used as described for 5a, only in second step
CHCl3 was used instead of CH2CL2. However, due to the high H2O
solubility of diethyl phosphate, a different work-up procedure was
used. After hydrolysis, the aqueous layer was extracted with CHCl3
(10 × 50 mL aliquots). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The resulting ma-
terial was distilled at 80 °C (0.7 mm Hg) (lit. 203 °C, 1 bar)27 yield-
ing 5c as a colorless oil in 60% yield (3.2 g).
31P NMR (81 MHz, CDCl3): δ = 7.51(s).
MS (EI+): m/z = 742.
Di-(6-{[4-(4-butylphenyl)azo]-phenoxy}-hexyl) Phosphonate
(2e)
An identical protocol as described for 2a was followed. The result-
ing yellow crystals were isolated in 70% yield (0.26 g).
Mp 106–109 °C.
1H NMR (200 MHz, CDCl3): δ = 1.30 (d, J = 7.2, 1.0 Hz, 6 H), 4.06
(m, 4 H), 12.54 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 15.8 (d, J = 7.2 Hz), 63.4 (d,
J = 5.7 Hz).
1H NMR (200 MHz, CDCl3): δ = 0.94 (t, J = 7.2 Hz, 6 H), 1.29–
1.86 (m, 24 H), 2.68 (t, J = 7.7, 4 H), 4.03–4.15 (m, 8 H), 6.83 (d,
J = 693 Hz, 1 H), 6.94–7.00 (m, 4 H), 7.21–7.31 (m, 4 H), 7.77–
7.81 (m, 4 H), 7.85–7.92 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 13.9, 22.3, 25.3, 25.6, 29.0, 30.3
(d, J = 6.5 Hz.), 33.5, 35.5, 65.6 (d, J = 6.1 Hz), 68.0, 114.6, 122.5,
124.5, 129.0, 145.8, 147.0, 151.0, 161.3.
31P NMR (81 MHz, CDCl3): δ = –0.13 ppm.
Di-(5-{[4-(4-butylphenyl)azo]-phenoxy}-pentyl)-phosphate (5d)
An identical protocol as described for 5a was followed. The result-
ing yellow crystals were isolated in a 56% yield (0.28 g).
31P NMR (81 MHz, CDCl3): δ = 7.50 (s).
MS (EI+): m/z = 770.
Mp 126–131 °C.
1H NMR (200 MHz, CDCl3): δ = 0.84 (t, J = 7.2 Hz, 6 H), 1.2–1.3
(m, 4 H), 1.45–1.79 (m, 16 H), 2.58 (t, J = 7.6 Hz, 4 H), 3.90–4.00
(m, 8 H), 6.86–6.92 (m, 4 H), 7.17–7.22 (m, 4 H), 7.65–7.79 (m, 8
H).
13C NMR (50 MHz, CDCl3): δ = 13.6, 21.9, 22.1, 28.5, 29.8 (d,
J = 6.9 Hz), 33.2, 35.3, 66.9 (d, J = 5.7 Hz), 67.8, 114.5, 122.3,
124.3, 128.9, 145.8, 146.7, 150.7, 161.2.
Di-{9-[(4-phenylazo)-phenoxy]-nonyl} phosphate (5a)
To 2a (0.42 mmol, 0.305 mg) in CCl4 (15 mL) was added Et3N (1.68
mmol, 234 µL, 170 mg) and i-Pr2EtN (0.42 µmol, 7.3 µL, 5.4 mg).
The mixture was stirred at r.t. for 1–3 d while monitoring the con-
version by means of 31P NMR. The volatile compounds were re-
moved by evaporation under reduced pressure. To the resulting
material 3, HOAc (10 mmol, 0.60 mL, 0.62 g) and Et3N (22 mmol,
3 mL, 2.2 g) were added. If necessary, CH2Cl2 was added to obtain
a clear solution. The mixture was stirred for 1–2 d leading to com-
plete conversion. The mixture was concentrated under reduced
pressure. The obtained crude product 4 was, subsequently, hydro-
lyzed by stirring in acidic H2O (pH 4–5, 100 mL) for 30 min. The
resulting mixture was extracted with CH2Cl2 (150 mL). The organic
layer was washed with brine (2 × 150 mL), dried over Na2SO4 and
concentrated under reduced pressure. The solid material was further
31P NMR (81 MHz, CDCl3): δ = –0.89 (s).
Anal. Calcd for C42H55N4O6P (742.9): C, 67.90; H, 7.46; N, 7.54.
Found: C, 67.75; H, 7.40; N, 7.45.
Di-(6-{[4-(4-butylphenyl)azo]-phenoxy}-hexanyl) Phosphate
(5e)
An identical protocol as described for 5a was followed. The result-
ing yellow crystals were isolated in a 73% yield (0.45 g).
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J. M. Kuiper et al.
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Mp 114–120 °C.
(13) Van der Marel, G.; van Boeckel, C. A. A.; Wille, G.; Boom,
J. H. Tetrahedron Lett, 1981, 22, 3887.
(14) Richter, W.; Ugi, I. Synthesis 1990, 661.
(15) Nikolaev, A. V.; Ivanova, I. A.; Shibaev, V. N.; Kochetkov,
N. K. Carbohydr. Res. 1990, 204, 65.
(16) Arbuzov, B. A. Pure Appl. Chem. 1964, 44, 3053.
(17) Nylen, P. Ber. Dtsch. Chem. Ges. 1924, 57, 1023.
(18) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc.
1945, 660.
1H NMR (200 MHz, CDCl3): δ = 0.94 (t, J = 7.2 Hz, 6 H), 1.32–
1.82 (m, 24 H), 2.68 (t, J = 7.6 Hz, 4 H), 3.97–4.11 (m, 8 H), 6.95–
6.99 (m, 4 H), 7.27–7.31 (m, 4 H), 7.77–7.81 (m, 4 H), 7.85–7.90
(m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 13.9, 22.3, 25.2, 25.6, 29.1, 30.1
(d, J = 6.9 Hz), 33.4, 35.5, 67.5 (d, J = 5.7 Hz), 68.0, 114.6, 122.5,
124.5, 129.0, 145.7, 146.9, 151.0, 161.3.
31P NMR (81 MHz, CDCl3): δ = 1.09 (s).
(19) Stereochemical studies have shown that the initially formed
trichloromethylesters can react either with nucleophiles
present or alternatively if no other nucleophiles are present
with the chloride formed, the latter leading to the formation
of phosphoric chlorides with retention of configuration with
respect to the phosphonate (double inversion) see:
(a) Hulst, R.; de Vries, N. K.; Feringa, B. L. Angew. Chem.
Int. Ed. Engl. 1992, 31, 1092. (b) Hulst, R.; Zijlstra, R. W.
J.; Feringa, B. L.; de Vries, N. K.; ten Hoeve, W.; Wijnberg,
H. Tetrahedron Lett. 1993, 34, 1339. (c) Hulst, R.; Zijlstra,
R. W. J.; de Vries, N. K.; Feringa, B. L. Tetrahedron:
Asymmetry 1994, 5, 1994.
(20) The smoothness of homomeric anhydride formation
(between two phosphonate entities) as an undesired side
reaction during functionalization has been outlined before,
see: Hulst, R.; Visser, J. M.; de Vries, N. K.; Zijlstra, R. W.
J.; Kooijman, H.; Smeets, W.; Spek, A. L.; Feringa, B. L. J.
Am. Chem. Soc. 2000, 122, 3135.
(21) Due to the high solubility of diethyl phosphate in H2O a
lower isolated yield was obtained than expected. Continuous
extraction will likely increase the yield considerably.
(22) Motoi, M.; Noguchi, K.; Arano, A.; Kanoh, S.; Ueyama, A.
Bull. Chem. Soc. Jpn. 1993, 66, 1778.
(23) 5-Bromobutan-1-ol was prepared by a literature procedure:
Chong, M.; Heuft, M. A.; Rabbat, P. J. Org. Chem. 2000, 65,
5837.
Anal. Calcd for C44H59N4O6P (770.95): C, 68.55; H, 7.71; N, 7.27.
Found: C, 68.67; H, 7.71; N, 7.28.
Acknowledgment
We are grateful to MSC+ for financial support.
References
(1) Kunitake, T.; Okahata, Y. Bull. Chem. Soc. Jpn. 1978, 51,
1877.
(2) Mortara, R. A.; Quina, F. H.; Chaimovich, H. Biochem.
Biophys. Res. Commun. 1978, 81, 1080.
(3) Wagenaar, A.; Rupert, L. A. M.; Engberts, J. B. F. N. J. Org.
Chem. 1989, 54, 2638.
(4) (a) Sasse, K. In Houben-Weyl, 4th ed., Vol 12/2; Müller, E.,
Ed.; Thieme: Stuttgart, 1964, 226; and references cited
therein. (b) Gallenkamp, B.; Hofer, W.; Krüger, B.-W.;
Maurer, F.; Pfister, T. In Houben-Weyl, 4th ed., Vol. E2;
Regitz, M., Ed.; Thieme: Stuttgart, 1982, 498; and
references cited therein.
(5) Ramirez, F.; Marecek, J. F.; Cheng, K. Phosphorus Sulfur
Relat. Elem. 1978, 4, 43; and references cited therein.
(6) Garegg, P. J.; Regberg, T.; Stawinski, J.; Strömberg, R. J.
Chem. Soc., Perkin Trans 1 1987, 1269.
(7) Birault, V.; Pozzi, G.; Plobeck, N.; Eifler, S.; Schmutz, M.;
Palanché, T.; Raya, J.; Brisson, A.; Nakatani, Y.; Ourisson,
G. Chem.–Eur. J. 1996, 2, 789.
(8) Nelson, A. K.; Toy, A. D. F. Inorg. Chem. 1963, 2, 775.
(9) Bauman, R. A. Synthesis 1974, 870.
(24) Floch, V.; Le Bolc’h, G.; Gable-Guillaume, C.; Le Bris, N.;
Yaouanc, J.-J.; des Abbayes, H.; Férec, C.; Clément, J.-J.
Eur. J. Med. Chem. 1998, 33, 923.
(25) The oleyl alcohol was obtained by reduction of oleic acid:
Pissas, D.; Dias, P.; Mikros, E. Magn. Reson. Chem. 1994,
32, 263.
(26) Nudelman, A.; Gnizi, E.; Katz, Y.; Azulai, Y.; Cohen-
Ohana, M.; Zhuk, R.; Sampson, S. R.; Langzam, L.; Fibach,
E.; Prus, E.; Pugach, V.; Rephaeli, A. Eur. J. Med. Chem.
2001, 36, 63.
(10) Smits, E.; Wagenaar, A. unpublished results.
(11) Tirri, L. J.; Schmidt, P. C.; Pullarkat, R. K.; Brockerhoff, H.
Lipids 1977, 12, 863.
(12) Smits, E.; Blandamar, M. J.; Briggs, B.; Cullis, P. M.;
Engberts, J. B. F. N. Recl. Trav. Chim. Pays-Bas 1996, 115,
37.
(27) Diethyl phosphate is available from Supelco.
Synthesis 2003, No. 5, 695–698 ISSN 0039-7881 © Thieme Stuttgart · New York