New synthetic approach to (o-hydroxyphenyl)methylphosphonic acid derivatives

Article abstract of DOI:10.1070/mc2003v013n04abeh001784

2,6-Dimethylphenols and 5,5′-dimethyl-6,6′-spirobiindanol react with diethylphosphite to give phosphates, which are easily transformed by LDA to (o-hydroxyphenyl)methylphosphonates.

Full text of DOI:10.1070/mc2003v013n04abeh001784

, 2003, 13(4), 182–183
New synthetic approach to (o-hydroxyphenyl)methylphosphonic acid derivatives
Giuseppe A. Consiglio, Salvatore Failla* and Paolo Finocchiaro
Dipartimento di Metodologie Fisiche e Chimiche per l’Ingegneria, Facolta’ di Ingegneria (Sede Enna), Universita’ di Catania,
95125 Catania, Italy. E-mail: sfailla@dmfci.unict.it
10.1070/MC2003v013n04ABEH001784
2,6-Dimethylphenols and 5,5'-dimethyl-6,6'-spirobiindanol react with diethylphosphite to give phosphates, which are easily trans-
formed by LDA to (o-hydroxyphenyl)methylphosphonates.
(o-Hydroxyphenyl)methylphosphonic acids are compounds with
significant binding properties towards heavy metals1 and lan-
thanides.2 These compounds can be prepared by reaction of
NBS
CCl4
benzyl halides with trialkyl phosphites according to the Michaelis–
Arbuzov reaction.3 For phenolic benzylphosphonic acids, espe-
BrH2C
OCOMe MeOCO
CH2Br
OCOMe
cially with the phenolic OH in the ortho-position relative to the
phosphonomethyl group, the direct reaction of o-hydroxybenzyl
alcohols with trialkyl phosphites is also possible.4,5
MeOCO
3
4
Our interest in phosphonic acid derivatives led us to the
synthesis of new building blocks bearing phosphonic groups,6
one of which is spirobiindane biphosphonate unit 1. This dis-
symetric molecule containing ancillary groups (phosphonic)
shows flame-retarding properties for epoxy resins,7 and, after
the hydrolysis to a monoester, opens new frontiers in applica-
tions as a negatively charged receptor.8,9
P(OEt)3
O
O
O
O
P
O
O
P
MeOCO
OCOMe
5
O
O
O
K2CO3
P
P
O
O
O
HO
OH
O
1
O
O
P
O
O
P
O
HO
OH
O
O
P
O
2
O
O
Scheme 1
P
HO
OH
ceptually based on the phosphorilation of the OH phenolic
group, which yields the phosphate derivative; the use of lithium
salts at low temperature, in case of bis(orthomethyl)-substituted
phenols rearranges the phosphate to the benzylic phosphonate
as reported in Scheme 2.‡
The first step proceeds in almost quantitative yield; the
second one, which represents the crucial step, occurs with a
60–70% yield depending on the starting phenols. We found that
the yields of (o-hydroxyphenyl)methylphosphonic acid deriva-
tives are little affected by the molar ratio LDA:phosphate. On
going from a stoichiometric amount to a large excess of LDA,
the best results were obtained when a molar ratio of 4:1
(LDA:phosphate) was used. In other words, the treatment of
phosphate esters with an excess of lithium diisopropylamide
O
2
In search for novel building blocks to be incorporated into
new types of molecular scaffolds, we have been attracted by
compound 2, where the phosphonic groups are attached to the
benzylic methylenes of the spirobiindane frame.
Here, we report on a new and general one-pot procedure
for the synthesis of (o-hydroxyphenyl)methylphosphonic acid
derivatives using ortho-disubstituted methyl phenol and lithium
diisopropylamide (LDA), with the idea of synthesising chiral
bis-chelating phosphonates, which can include neutral guests and
act as ligands for lanthanides. Furthermore, these molecules,
after hydrolysis to the corresponding bis-monoesters, could
become water-soluble receptors for positively charged mole-
cules and thus act as potential resolving agents for antipods of
biologically relevant molecules.
Compound 3 was prepared according to the published procedure.11
5,5'-Dibromomethyl-6,6'-diacetoxy-3,3,3',3'-tetramethyl-1,1'-spirobi-
indane 4: 0.75 g (65%), mp 170–172 °C. H NMR (CDCl3) d: 7.18 (s,
2H, spiroArH), 6.54 (s, 2H, spiroArH), 4.42 (dd, 4H, CH2Br, JHH
†
As an example, Scheme 1† demonstrates the most usual
synthetic pathway for obtaining compoud 2. The first step pro-
ceeds with a 60% yield, and the second one, with a 40% yield.
Then, the hydrolysis of ester 5 affords compound 2 with only a
18% overall yield.
Therefore, considering our experience in the production of
ortho-hydroxyaryl phosphonates6 by the 1,3-phosporotropic re-
arrangement reaction performed on aryl phosphates and LDA
at a low temperature, we decided to follow a more simple and
direct way to compound 2, i.e., to use the LDA rearrangement
for the preparation of (o-hydroxyphenyl)methylphosphonic acids.
In order to optimise the new reaction, mesitol and 2,6-dimethyl-
phenol were chosen as model compounds. The synthesis is con-
1
2
10 Hz), 2.29 (s, 6H, MeCO), 2.31 (dd, 4H, spiroCH2, JHH 13 Hz), 1.4
(s, 6H, spiroMe), 1.37 (s, 6H, spiroMe). 13C NMR (CDCl3) d: 169.06,
152.03, 150.18, 148.6, 128.44, 124.15, 118.76, 59.14, 57.54, 43.36,
31.52, 30.16, 28.48, 26.91, 20.29. FAB-MS, m/z (%): 579 (8) [M + H]+,
601 (70) [M + Na]+.
5,5'-Diethylphosphonomethyl-6,6'-diacetoxy-3,3,3',3'-tetramethyl-1,1'-
spirobiindane 5: 0.44 g (40%). 1H NMR (CDCl3) d: 7.15 (d, 2H, spiroArH,
4JHP 2.8 Hz), 6.53 (s, 2H, spiroArH), 4.03 (m, 8H, POCH2Me), 3.09
(m, 4H, CH2P), 2.28 (dd, 4H, spiroCH2, JHH 13.3 Hz), 1.36 (s, 6H,
spiroMe), 1.32 (s, 6H, spiroMe), 1.25 (t, 6H, POCH2Me, JHH 7 Hz),
2
3
3
1.24 (t, 6H, POCH2Me, JHH 7.2 Hz). FAB-MS, m/z (%): 693.72 (25)
[M + H]+, 715 (23) [M + Na]+.
– 182 –

phate ester upon treatment with diethyl phosphite and CCl4 in
the presence of triethylamine, and then rearranged to crystalline
product 2 by treatment of the diphosphate with a strong base
(LDA). The possibility that the phosphonic group goes to the
7,7'-position of the spirobiindanol skeleton by 1,3-rearrange-
ment is very low and impossible because of the high steric
congestion of such aromatic carbon atoms.
Phosphorus, carbon and proton NMR data provided con-
vincing evidence for the structure assigned. Diphosphate of
compound 2 showed a single phosphorus resonance at d
–5.76 ppm, while the rearrangement product 2 showed a single
phosphorus resonance at d 30.22 ppm, which is also so far from
the resonance d 22.12 ppm of compound 1, where the phos-
phorus atoms are directly attached to the aromatic carbons.
In summary, our new general synthetic procedure allows to
produce o-hydroxyphenyl methyl phosphonic acids in a very
convenient and easy way.
O
O
P
O
OH
R
O
R
OH
R
O
P
i
ii, iii
O
O
6 R = H
7 R = Me
Scheme 2 Reagents and conditions: i, HP(O)(OEt)2/CCl4, NEt3, 0 °C; ii,
LDA/THF, –78 °C; iii, saturated NH4Cl/H2O.
generates the methyl anion, which undergoes migration of the
phosphorus from oxygen to carbon. Although O ® C migrations
of phosphorus are not without precedent,6,10 this new reaction
represents the first example of a phosphate ® phosphonate
rearrangement involving the methyl group.
This study was supported by MURST.
A comment on the selectivity of the reaction is necessary. In
principle, when 2,6-dimethylphenol is employed as a substrate,
if a double 1,3-sigmatropic rearrangement of the phosphate group
is operating, one should expect that the compound containing
the phosphonic group attached to the aromatic carbon in the
para-position of the phenol must be formed. No evidence was
found for the formation of such a derivative, indicating that a
double sigmatropic rearrangement is not operating.
References
1
F. Benghanem, S. Chafaa, G. M. Bouet and A. M. Khan, Phosphorus
Sulfur Silicon Relat. Elem., 2001, 170, 159.
2
3
E. Bentouhami, G. M. Bouet and A. M. Khan, Talanta, 2002, 57, 545.
V. Böhmer, W. Voft, S. Chafaa, J. Meullemeestre, M. J. Schwing and
F. Vierling, Helv. Chim. Acta, 1993, 76, 139.
4
A. B. Ageeva and B. E. Ivanov, Izv. Akad. Nauk SSSR, Ser. Khim.,
1967, 1494 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1967, 16, 1443).
W. Vogt, Phosphorus Sulfur Relat. Elem., 1978, 5, 123.
G. A. Consiglio, S. Failla, P. Finocchiaro and V. Siracusa, Phosphorus
Sulfur Silicon Relat. Elem., 1998, 134/135, 413.
Then, using the synthetic procedure outlined in Scheme 2,
compound 2 was easily synthesised starting from 5,5'-dimethyl-
6,6'-spirobiindanol, which is readily converted into its diphos-
5
6
‡
7
8
9
A. D. La Rosa, S. Failla, P. Finocchiaro, A. Recca, V. Siracusa, J. T.
Carter and P. T. McGrail, J. Polym. Eng., 1999, 19, 151.
W. Wehner, T. Schrader, P. Finocchiaro, S. Failla and G. Consiglio,
Org. Lett., 2000, 2, 605.
T. Grawe, T. Schrader, P. Finocchiaro, G. Consiglio and S. Failla, Org.
Lett., 2001, 3, 1597.
General procedure for the synthesis of (o-hydroxyphenyl)methylphos-
phonic acid diethyl esters 2, 6 and 7. In a typical procedure, to a stirred
mixture of bis(hydroxyphenyl) derivatives (0.05 mol) and diethyl phos-
phite (0.11 mol) in carbon tetrachloride (100 ml) cooled at 0 °C, triethyl-
amine was added dropwise and the reaction temperature was main-
tained below 10 °C by external cooling. The mixture was stirred over-
night at room temperature; then, the ammonium salt formed was filtered
off and the organic solution was washed with 2 N sodium hydroxide and
water and dried over anhydrous Na2SO4. The removal of the solvent in
a vacuum left the bis(phosphate) precursor as a colourless oil, a part
(0.01 mol) of which in a THF solution (50 ml) was added from a drop-
ping funnel to a lithium diisopropylamide (LDA) (0.04 mol) solution in
100 ml of THF at –78 °C. After the addition was completed, the reaction
mixture was stirred at –78 °C for 6 h; then, the reaction mixture was
quenched with 200 ml of saturated aqueous ammonium chloride. The
organic mass was extracted with diethyl ether and chloroform and dried
over anhydrous Na2SO4; after evaporation of the solvents at reduced
pressure, it was purified by column chromatography on silica gel using
gradient elution with ethyl acetate in cyclohexane to give pure dialkyl-
(o-hydroxyaryl)methylphosphonate.
10 B. Dhawan and D. Redmore, J. Org. Chem., 1984, 49, 4018.
11 W. Baker and D. M. Besly, J. Chem. Soc., 1939, 1421.
5,5'-Diethylphosphonomethyl-6,6'-dihydroxy-3,3,3',3'-tetramethyl-1,1'-
1
spirobiindane 2: 3.65 g (60%), mp > 220 °C. H NMR (CDCl3) d: 6.82
4
(d, 2H, spiroArH, JHP 2 Hz), 6.38 (s, 2H, spiroArH), 4.03 (m, 8H,
POCH2Me), 3.21 (m, 4H, CH2P), 2.25 (dd, 4H, spiroCH2, 2JHH 13 Hz),
1.34 (s, 6H, spiroMe), 1.28 (s, 6H, spiroMe), 1.22 (m, 12H, POCH2Me).
13C NMR (CDCl3) d: 154.8 (d, JCP 5 Hz), 151.6, 144.95, 124.27 (d,
JCP 7.75 Hz), 117.62 (d, JCP 9.1 Hz), 114.53, 63.23 (d, JCP 6.75 Hz),
62.84 (d, JCP 6.87 Hz), 59.58, 42.91, 31.82, 30.4, 30.18 (d, 1JCP 136.5 Hz),
16.25. 31P NMR (CDCl3) d: 30.218. FAB-MS, m/z: 609.2 (100%) [M + H]+.
6-Methyl-2-phosphonomethylphenol 6: 1.68 g (65%). 1H NMR (CDCl3)
d: 7.05 (d, 1H, ArH, 3JHH 7.5 Hz), 6.88 (d, 1H, ArH, 3JHH 7.5 Hz), 6.76
3
(t, 1H, ArH, JHH 7.5 Hz), 4.02 (m, 4H, POCH2Me), 3.15 (d, 2H,
ArCH2P, 2JHP 21 Hz), 2.27 (s, 3H, ArMe), 1.24 (t, 6H, POCH2Me, 3JHH
7 Hz). 13C NMR (CDCl3) d: 153.69 (d, JHP 4.7 Hz), 130.19 (d, JHP 3.4 Hz),
128.79 (d, JHP 7.6 Hz), 128.05 (d, JHP 3.4 Hz), 120.52 (d, JHP 2.1 Hz),
1
118.32 (d, JHP 9.4 Hz), 62.96 (d, JHP 7.3 Hz), 30.12 (d, JHP 136.9 Hz),
16.30, 16.16 (d, JHP 6.0 Hz). 31P NMR (CDCl3) d: 30.204. FAB-MS,
m/z (%): 259.2 (99) [M + H]+.
4,6-Dimethyl-2-phosphonomethylphenol 7: 1.91 g (70%). 1H NMR
(CDCl3) d: 8.1 (s, 1H, ArOH), 6.87 (s, 1H, ArH), 6.69 (s, 1H, ArH), 4.05
2
(m, 4H, POCH2Me), 3.11 (d, 2H, ArCH2P, JHP 21 Hz), 2.24 (s, 3H,
ArMe), 2.21 (s, 3H, ArMe), 1.25 (t, 6H, POCH2Me, 3JHH 7 Hz). 13C NMR
(CDCl3) d: 151.39 (d, JHP 4.5 Hz), 130.92 (d, JHP 3.62 Hz), 129.677,
129.17 (d, JHP 8.25 Hz), 127.91 (d, JHP 3.25 Hz), 118.13 (d, JHP 9.12 Hz),
1
62.97 (d, JHP 6.75 Hz), 30.24 (d, JHP 136.5 Hz), 20.33, 16.26 (m).
31P NMR (CDCl3) d: 30.393. FAB-MS, m/z (%): 273.2 (99) [M + H]+.
Received: 28th April 2003; Com. 03/2110
– 183 –