One-pot synthesis of phosphonic acid diesters

Full text of DOI:10.1021/jo951308p

J . Org. Chem. 1996, 61, 6015-6017
6015
Sch em e 1
On e-P ot Syn th esis of P h osp h on ic Acid
Diester s
Aurelio Munoz,* Cathy Hubert, and J ean-Louis Luche
Laboratoire AMPERES, Bat. 2R1, Universite´ Paul Sabatier,
118 route de Narbonne, 31062 Toulouse Cedex, France
Received J uly 19, 1995 (Revised Manuscript Received May 10,
1996 )
Ta ble 1. P h osp h on a tes P r ep a r ed via Rea ction 1
Phosphonic acid diesters are useful intermediates in
chemistry,1 and finding new synthetic routes to these
compounds constitutes a valuable target. Known prepa-
rations include transesterification of easily available
members of the family,2 acidolyses or hydrolyses of
phosphorochloridites or mixed anhydrides,3-5 addition of
phosphonic acid to oxiranes,6 or alcoholysis of bis(N,N-
dimethylamino) phosphonate.7 Among these, the hy-
drolysis of phosphorochloridites, probably the more con-
venient synthetic access, requires the preliminary
preparation of the latter, with possible yield limitations.
This paper describes the direct reaction of phosphonic
acid with various hydroxy compounds in the presence of
dicyclohexylcarbodiimide (DCCI), which avoids the draw-
backs of the above-mentioned methods. Mixing the
reagents in tetrahydrofuran (THF) initiates a fast process
that, when monitored by 31P NMR spectroscopy, shows
the immediate replacement of the phosphonic acid signal
by a peak at 112.3 ppm corresponding to phosphorous
anhydride.8 A doublet assigned to the phosphonate ester
progressively grows as the reaction of P4O6 with the
hydroxyl compound proceeds (Scheme 1). After 1 h in
most cases, the remaining peaks are those of the expected
diester and minor amounts of monophosphonate as a side
product. Compounds 1-10 are prepared in good yields
by this method (Table 1). In the 31P NMR spectra, the
PH signals used to identify compounds 1, 2, 4-6, and
10, consist of two pseudotriplets (for 2, 10) or two
pseudoquintuplets (for 1 and 4-6).
These products are sensitive toward moisture, which
explains the presence in the crude mixture of minor
amounts (10-20%) of monophosphonates. However,
their low solubility allows a clean and easy separation.
The structures of all these compounds were established
by elemental analyses, NMR, and mass spectrometry. As
an example of the efficiency of the method, the labile
isopropylidene masking groups in compound 2 did not
suffer any cleavage. The unexpected complexity of the
13C NMR spectrum possibly reflects the existence of
conformers stabilized by hydrogen bonding (Chart 1).
Bis(trimethylsilyl) phosphonate was previously pre-
pared from phosphonic acid and bis(trimethylsilyl)-
amine.9 With the present method, the bis(triphenylsilyl)
a
Literature yields (in parentheses) are based on trichlorophos-
phane. In ppm. c Solvents: (A) C6D6; (B) THF; (C) CH2Cl2; (D)
b
CH3CN; (E) DMF. In Hz; q : quintuplet, t : triplet. e Reference
d
7. f Reference 4. From reaction 4. Reference 3.
g
h
Ch a r t 1
ester 3 was obtained in 75% yield by reaction 1 from the
cheap commercial triphenylsilanol.
(1) Kosolapoff, G. M.; Maier, L. Organic phosphorus compounds;
J ohn Wiley and Sons: New York, 1976; Vol. 7, pp 27-30.
(2) Oswald, A. A. Can. J . Chem. 1959, 37, 1498-1504.
(3) Nesterov, A. V.; Sabirova, R. A. J . Gen. Chem. USSR 1965, 35,
1967-1970.
In addition to the above examples of monofunctional
alcohols, difunctional compounds were reacted under the
specified conditions. 1,3-Propanediol gave the 6-mem-
bered ring ester 6. Triethyleneglycol and 1,10-decanediol
provide, respectively, macrocyclic esters 4 and 5 (Chart
2), as shown by their analytical and spectral data. The
molecular weight (325) of 4, determined by cryoscopy,
indicates the presence of the mono and dinuclear com-
pounds in relative amounts of 1:2, with minor quantities
of tri- and tetranuclear macro rings detected in the mass
spectrum.
(4) Zwierzak, A. Can. J . Chem. 1967, 45, 2501-2512.
(5) Nefant'ev, E. E.; Fursenko, I. V. J . Gen. Chem. USSR 1968, 38,
1251-1255.
(6) Klosinski, P. Tetrahedron Lett. 1990, 31, 2025-2028.
(7) Page, P.; Mazieres, M. R.; Bellan, J .; Sanchez, M.; Chaudret, B.
Phosphorus, Sulfur Silicon 1992, 70, 205-210.
(8) Crutchfield, M. M.; Dungan, C. H.; Mark, V.; Van Wazer, J . R.
31P Nuclear Magnetic Resonance, Topics in phosphorus chemistry; J ohn
Wiley and Sons: New York, 1967; Vol. 5, p 256.
(9) Lebedev, E. P.; Pudovik, A. N.; Tsyganov, B. N.; Nazmutdenov,
R. Ya.; Romanov, G.V. J . Gen. Chem. USSR 1977, 47, 698-701.
S0022-3263(95)01308-9 CCC: $12.00 © 1996 American Chemical Society

6016 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
Ch a r t 2
steps, as in previous methods. Dicyclohexylurea, the sole
byproduct is easily removed by precipitation, which can
be made easier by ultrasonic irradiation. The mild
conditions are compatible with the presence of sensitive
protecting groups, and the versatility of the reaction
makes it useful for synthetic purposes.
Exp er im en ta l Section
Commercially available reagents were used as received.
Phosphonic acid was dried in a microwave oven for 20 min. THF,
acetonitrile, and ethyl acetate were dried on 3 Å molecular
sieves. THF was kept on sodium wire. Melting points are not
corrected. 1H, 13C, and 31P NMR spectra were recorded with
TMS as internal (1H and 13C) and 85% H3PO4 as external (31P)
standards. Cryoscopic measurements were carried out in DMSO
(analytical grade dried on 3 Å molecular sieves; mp 18.49 °C; K
[measured with phenylphosphonic acid] ) 4.21 K‚kg‚mol-1
(lit.15,16 4.07-4.39 K‚kg‚mol-1). Low-resolution mass spectra
were recorded with chemical ionization (CH4). High-resolution
spectra were recorded with electron impact in a V.G. Autostec
Q. apparatus (8000 < resolution < 10 000, 70 eV), in the Centre
d’Etudes de Structure, d’Analyse de Molecules Organiques,
Talence, France). Elemental analyses were carried out by the
“Service de microanalyses, Ecole Nationale Supe´rieure de Chim-
ie de Toulouse”. Sonications were effected in a 47 kHz Kerry
ultrasonic bath at room temperature.
Sch em e 2
Sch em e 3
P r ep a r a t ion of P h osp h on a t es 1, 2, 4-6, 8, a n d 10.
Gen er a l P r oced u r e a . Phosphonic acid (0.42 g, 5 mmol) in 5
mL of THF was rapidly added to a solution of the hydroxyl
compound (5 mmol of diol or 10 mmol of alcohol) and DCCI (2.06
g, 10 mmol) in 15 mL of the same solvent. An exothermic
reaction took place, and the mixture was kept at room temper-
ature with liquid nitrogen. After the 31P NMR spectrum had
shown the absence of a low field signal, the crude mixture was
sonicated for 30-60 min at room temperature. Dicyclohexylurea
was filtered off, and then the solvent was evaporated to give
the phosphonates in an analytical purity as indicated below in
each individual case.
P r oced u r e b for Com p ou n d s 3 a n d 11. DCCI (2.06 g, 10
mmol) in 10 mL of THF was added to phosphonic acid (0.42 g,
5 mmol) and hydroxyl compound (10 mmol of triphenylsilanol
and 5 mmol of salicylic or benzhydroxamic acids) in THF (10
mL). An exothermic reaction took place. The reaction was
completed under sonication, and then isolation and purification
were effected as described below.
In the case of 5, the cryoscopic measurement (average
molecular weight 727) shows a predominance (2:1) of the
trinuclear compound over the tetranuclear one. These
compounds could not be separated. Analogous large ring
compounds were previously prepared from aryldichloro-
phosphane oxide and triethylene glycol.10
Phosphonate 7, previously described as a phosphite,3
could be obtained quantitatively from salicylic acid;
however, it was contaminated by ca. 5% dicyclohexylurea.
An analytical purity product resulted from the ultra-
sound-induced precipitation of the contaminant from the
ethyl acetate solution or by an alternate reaction between
trichlorophosphane and salicylic acid in the presence of
dry sodium acetate (2 equiv), as depicted in Scheme 2.
References to organophosphorus compounds derived
from the hindered benzopinacol are not frequent.11 Reac-
tion 1 applies to this compound, although it proceeds
slowly to give phosphonate 9. Heating to 70-80 °C or
sonication significantly increases the reaction rate. On
the other hand, similar reactions starting from catechol
and R-hydroxyisobutyric and benzhydroxamic acids lead
to the corresponding known spirophosphoranes.12-14 When
applied to benzhydroxamic acid, the present method
constitutes an alternate access to these spiranic mol-
ecules, as illustrated by the preparation of compound 11
(Scheme 3).14
Bis(h exa d ecyl) P h osp h on a te (1).7 The reaction was run
in THF:CH2Cl2 (1:1). After precipitation, the urea was filtered
off at 50 °C and washed with CH2Cl2 (10 mL). The solvent was
evaporated and the solid dissolved in hot pentane (10 mL). The
residual urea was filtered off, and then compound 1 precipitated.
Yield: 70%. Mp: 51-53 °C (lit. not given).
Bis(1,2:5,6-d iisop r op ylid en e-D-glu cose) P h osp h on a te (2).
The reaction mixture was allowed to stand at -5 °C for 24 h,
and then the urea was removed. Addition of pentane precipi-
tated the residual urea and small amounts of 2. After decanta-
tion and evaporation of the supernatant at 0.01 Torr, 2 was
obtained as a hygroscopic powder, in 57% yield. Small amounts
of the monophosphonate (5-10%) were eliminated by addition
of an equivalent quantity of triethylamine to the crude dissolved
in diethyl ether and filtration of the salt. NMR spectra
confirmed the absence of dicyclohexylurea. 1H NMR (C6D6, 80.1
1
3
MHz): 6.91 (d, 1 H, J PH ) 726 Hz), 5.82 (d, 2 H, J PH ) 3 Hz),
4.93-3.87 (m, 12 H), 1.38, 1.31, 1.22 (24 H) ppm. 13C NMR
(C6D6, 50.32 MHz): 112.56, 112.45, 111.68, 109.81, 109.7, 109.4,
105.8 (d, 3J PC ) 9.4 Hz), 85.88, 84.38, 81.12, 81.03 (d, 3J PC ) 6.1
Hz), 79.3 (d, 2J PC ) 4.7 Hz), 78.81 (d, 2J PC ) 6.7 Hz), 75.28, 73.58,
73.00, 72.65, 67.89, 67.84, 67.62, 27.14, 27.04, 26.91, 26.75, 26.33,
26.18, 25.48, 25.23 ppm. MS (DCI) m/ z: 567 (M + 1, 100), 509,
261. HRMS: calcd for C24H39O13P 567.2206, found 567.2183.
Bis(tr ip h en ylsilyl) P h osp h on a te (3). With the above
purification procedure, a microcrystalline powder was obtained
In summary, reaction 1 has the advantage to start from
cheap commercial compounds and to avoid intermediate
(10) El Malouli, B. M.; Hannioui, A.; Peiffer, G.; Samat, A.; Pannell,
K. H. Synth. Commun. 1993, 23, 2273-2278.
(11) Meyer, T. G.; Fischer, A.; J ones, P. G.; Schmutzler, R. Z.
Naturforsch. 1993, 48b, 659-671.
(12) Gallagher, M.; Munoz, A.; Gence, G.; Koenig, M. J . Chem. Soc.,
Chem. Commun. 1976, 321-322.
(13) Koenig, M.; Munoz, A.; Garrigues, B.; Wolf, R. Phosphorus
Sulfur 1979, 6, 435-451.
(15) Garnsey, R.; Prue, J . E. Trans Faraday Soc. 1968, 64, 1206-
1218.
(16) Munoz, A.; Lamande, L.; Koenig, M.; Wolf, R.; Brossas, J .
Phosphorus Sulfur 1981, 11, 71-86.
(14) Fluck, E.; Vargas, N. Z. Anorg. Allg. Chem. 1977, 437, 53-59.
Hinrichs, E. V.; Ugi, I. J . Chem. Res., Synop. 1978, 338; J . Chem. Res.,
Miniprint 1978, 3973-3993.

Notes
J . Org. Chem., Vol. 61, No. 17, 1996 6017
in 75% yield. Mp: 150-151 °C. 1H NMR (C6D6, 80.1 MHz):
(2) From phosphonic acid, procedure b was followed. After
completion, urea was filtered off. The 31P NMR spectrum
exhibited the doublet of product 7. Solvent evaporation gave a
white sticky powder, washed with Et2O (10 mL). The product
separated as a microcrystalline powder that was taken up in
ethyl acetate and sonicated for 30 min to force the residual urea
to crystallize. After its removal, diethyl ether was added, and
compound 7 was crystallized by cooling to -20 °C. Yield: 50%.
2-Oxo-4,4,5,5-t et r a m et h yl-1,3,2-d ioxa p h osp h ola n e (8).4
The reaction was run in THF without cooling. Urea was
separated after sonication for 1 h. Solvent evaporation gave a
powder that was washed with diisopropyl ether (10 mL) and then
dissolved in ethyl acetate. Residual urea was removed, and 8
was isolated as microcrystals after solvent evaporation. Yield:
70%. Mp: 98-102 °C. 1H NMR (CDCl3, 80.1 MHz): 7.2 (d, 1H,
1J PH ) 706 Hz), 1.44 and 1.34 (ds, 12 H) ppm. 13C NMR (CDCl3,
1
7.1 (d, 1H, PH, J PH ) 710 Hz), 7.83-7.58, 7.2-7.0 (m, 30 H)
ppm. 13C NMR (CDCl3, 50.32 MHz): 135.44, 132.05, 130.67,
128.20 ppm. MS m/ z: 627 (M + 29, 10), 599 (M + 1, 20), 521
(100). HRMS: calcd for C36H31O3PSi2 597.1471, found 597.1473.
Tr ieth ylen eglycol P h osp h on a te 4: Rea ction Ru n in
THF :CH2Cl2 (1:1). After separation of urea and solvent evapo-
ration, the resulting oil was dissolved in acetonitrile (5 mL) and
kept at 0 °C for 24 h. Residual urea was removed and the
solvent evaporated to give an oil (60%). 1H NMR (CDCl3, 80.1
MHz): 6.9 (d, 1 H, 1J PH ) 713 Hz), 4.28-4.02 (m, 4 H), 3.7, 3.63,
3.60 (8 H) ppm. 13C NMR (CDCl3, 50.32 MHz): 70.50, 70.17 (d,
2
3J PC ) 5.2 Hz), 64.47 (d, J PC ) 5.7 Hz) ppm. MS (DCI) m/ z:
785 (4M + 1, <1), 589 (3M + 1, 5), 393 (2M + 1, 75), 197 (M +
1, 100). MW (cryoscopic) 325. Anal. Calcd for (C6H13O5P)n: C,
36.73; H, 6.68. Found: C, 36.54; H, 7.06.
3
3
50.32 MHz): 88.96, 24.68 (d, J PC ) 3.6 Hz), 23.97 (d, J PC
5.4 Hz) ppm. MS (DCI) m/ z: 165 (M + 1, 100).
)
1,10-Deca n ed iol P h osp h on a te 5. After urea removal and
THF evaporation, the thick oil was dissolved in ethyl acetate (5
mL). The residues of urea were filtered off, and the solvent was
removed to give an oil (60%) that solidified at 0 °C. 1H NMR
(CDCl3, 80.1 MHz): 6.75 (d, 1 H, 1J PH ) 694 Hz), 4.06-3.95 (m,
4 H), 1.84-1.25 (m, 16 H) ppm. 13C NMR (CDCl3, 50.32 MHz):
2-Oxo-4,4,5,5-tetr aph en yl-1,3,2-dioxaph osph olan e (9). The
reaction was run in THF without cooling. After precipitation
of urea, the mixture was stirred at 70-80 °C for 6 h, urea was
removed, and the solvent was evaporated. The powder was
dissolved in ethyl acetate (10 mL) and sonicated for 30 min to
crystallize the urea. The solvent was evaporated from the
filtrate, and the resulting powder was dispersed in diethyl ether
(10 mL) and kept at 0 °C for 24 h. Compound 9 was filtered
and dried under vacuum. Yield: 65%. Mp: 176-178 °C. 1H
2
3
65.81 (d, J PC ) 5.5 Hz), 30.4 (d, J PC ) 6.2 Hz), 29.38, 29.07,
25.48 ppm. MS (DCI) m/ z: 881 (4M + 1, 3), 661 (3M + 1, 25),
441 (2M + 1, 100), 221 (M + 1, 30). MW (cryscopic) 727. Anal.
Calcd for (C10H21O3P)n: C, 54.54; H, 9.61. Found: C, 54.25; H,
9.79.
1
2-Oxo-1,3,2-d ioxa p h osp h or in a n e (6):4 purified as for com-
NMR (CDCl3, 80.1 MHz): 7.32 (d, 1 H, J PH ) 727 Hz), 7.46-
7.00 (m, 20 H) ppm. 13C NMR (C6D6, 50.32 MHz): 141.3 (d, 3J PC
) 5 Hz), 140.37 (d, 3J PC ) 4.5 Hz), 129.49, 129.14, 128.39, 128.18,
128.02, 127.6, 127.43, 126.95, 83.63 ppm. MS (DCI) m/ z: 413
(M + 1, 100), 183 (100). Anal. Calcd for C26H21O3P: C, 75.73;
H, 5.13. Found: C, 75.98; H, 5.45.
pound 2 to give needles (65%). Mp: 28-30 °C. 1H NMR (CDCl3,
1
80.1 MHz): 6.8 (d, 1 H, J PH ) 678 Hz), 4.56-4.21 (m, 2 H),
2.32-1.83 (m, 2 H) ppm. 13C NMR (CDCl3, 50.32 MHz): 67.27
2
3
(d, J PC ) 6.2 Hz), 25.93 (d, J PC ) 8.1 Hz) ppm. MS (DCI)
m/ z: 123 (M + 1, 100).
2,4-Dioxo-5,6-ben zo-1,3,2-d ioxa p h osp h or in a n e (7).3 (1)
Salicylic acid (1.38 g, 10 mmol), trichlorophosphane (1.4 g, 10
mmol), and anhydrous sodium acetate (1.64 g, 20 mmol) were
stirred in 25 mL of diethyl ether for 4 h. After this period, the
31P NMR peak of PCl3 was replaced by those of 2-chloro-4-oxo-
5,6-benzo-1,3,2-dioxaphosphorinane (148 ppm, 65%),17 2-acetoxy-
4-oxo-5,6-benzo-1,3,2-dioxaphosphorinane (114.5 ppm, 25%),18
and phosphonate 7 [-3.8 ppm (proton decoupled), 10%]. Pre-
cipitated NaCl was separated by centrifugation, and the super-
natant was kept under an inert atmosphere at room tempera-
ture. Compound 7 crystallized as needles that were separated,
Bis(1,2:5,6-d iisop r op ylid en e-D-m a n n itol) P h osp h on a te
(10). After urea separation and concentration of the filtrate,
pentane (5 mL) was added. Compound 10 precipitated at -20
°C as microcrystals. Yield: 60%. Mp: 72-74 °C. 1H NMR
1
(C6D6, 200 MHz): 7.24 (d, 1H, J PH ) 727.4 Hz), 4.17, 3.61 (m,
8H), 1.27 (s, 3H), 1.25 (s, 3H), 1.09 (s, 3H), 1.01 (s, 3H) ppm. 13
C
NMR (C6D6, 50.32 MHz): 110.5, 110.4, 81.5, 79.2, 75.4, 74.5,
66.74, 64.77, 26.74, 26.19, 24.86, 24.33 ppm. MS m/ z: 309 (M
+ 1, 100). Anal. Calcd for C12H21O7P: C, 46.75; H, 6.86.
Found: C, 46.41; H, 7.02.
2,7-Dip h en yl-3,8-d ia za -1,4,6,9-t et r a oxa -5-h yd r id o-5λ5-
ph osph aspir o[4.4]2,3,7,8-n on en e (11).14 Benzhydroxamic acid
(0.7 g, 5 mmol) in a 1:1 mixture of THF:CH2Cl2 was added to
the phosphonic acid (0.42 g, 5 mmol) DCCI (2.06 g, 10 mmol)
mixture. After 30 min at rt, the urea was filtered off. The
solvents were evaporated to give a sticky powder that was
washed with benzene (15 mL). An oil was separated, and
evaporation of the supernatant gave 11 in 62% yield. Mp: 136-
138 °C (lit.14 mp 140 °C). 1H NMR (CDCl3, 80.1 MHz): 8.78 (d,
washed with Et2O, and dried under vacuum. Yield: 80%. Mp:
1
120 °C dec. 1H NMR (CDCl3, 80.1 MHz): 7.62 (d, 1H, J PH
)
763 Hz), 8.9-7.16 (m, 4 H) ppm. 13C NMR (CDCl3, 50.32
2
2
MHz): 162.07, 153.92 (d, J PC ) 7 Hz), 151.15 (d, J PC ) 5.6
Hz), 138.51, 136.29, 131.96, 130.74, 126.21, 119.32, 117.55,
4
3
119.56 (d, J PC ) 9.6 Hz), 113.52 (d, J PC ) 4.8 Hz). MS (DCI)
m/ z: 185 (M + 1, 30), 139 (100).
1
1H, J PH ) 889 Hz), 7.96-7.8, 7.44-7.24 (m, 10 H) ppm. 13C
(17) Crutchfield, M. M.; Dungan, C. H.; Letcher, J . H.; Mark, V.;
Van Wazer, J . R. 31P Nuclear Magnetic Resonance, Topics in phospho-
rus chemistry; J ohn Wiley and Sons: New York, 1967; Vol. 5, p 325.
(18) 2-Acetoxy-4-oxo-5,6-benzo-1,3,2-dioxaphosphorinane was pre-
pared from trichlorophosphane (5 mmol), salicylic acid (5 mmol), and
sodium acetate (15 mmol) in diethyl ether. Crystals are obtained after
filtration of NaCl and solvent evaporation. Mp: 73-76 °C (lit.3 mp
72-74 °C). 31P NMR (CDCl3, 32.44 MHz): 114.5. 1H NMR (CDCl3, 80.1
MHz): 8.11-7.04 (m, 4 H), 2.12 (d, 3 H, 4J PH ) 1.2 Hz) ppm. 13C NMR
2
NMR (C6D6, 50.32 MHz): 165.0 (d, J PC ) 8.9 Hz), 132.42,
3
128.85, 126.73, 124.32 (d, J PC ) 3.7 Hz) ppm.
Ack n ow led gm en t. The authors thank CNRS (EP
52) for financial support, Drs. Tran Le Tran, A. Dall'Ava,
S. Richelme, C. Claparos, G. Bourgeois, and E. Leroy
for spectral measurements, J . Bourdil for elemental
analysis, and B. Garrigues for useful comments.
2
2
(CDCl3, 50.32 MHz): 169.7 (d, J PC ) 6.3 Hz), 153.0 (d, J PC ) 6.7
3
3
Hz), 137.05, 131.08 (d, J PC ) 2.8 Hz), 124.83, 119.6, 116.8 (d, J PC
11.7 Hz), 21.8 (d, J PC ) 2.2 Hz) ppm.
)
3
J O951308P