Dealkylation of dialkyl phosphonates with boron tribromide

Article abstract of DOI:10.1055/s-2001-12354

Boron tribromide cleanly and quantitatively converts dimethyl-, diethyl-, diisopropyl-, and ditertiobutyl phosphonates RP(O)(OR')₂ into the corresponding phosphonic acids RP(O)(OH)₂ via methanolysis. The use of boron tribromide is compatible with a variety of functionalities in the R group.

Full text of DOI:10.1055/s-2001-12354

SHORT PAPER
553
Dealkylation of Dialkyl Phosphonates with Boron Tribromide
Noëlle Gauvry, Jacques Mortier*
Université du Maine and CNRS, Laboratoire de synthèse organique (UMR 6011), Faculté des sciences, avenue Olivier Messiaen, 72085
Le Mans Cedex 9, France
Fax +33(2)43833366; E-mail : jacques.mortier@aviion.univ-lemans.fr
Received 31 October 2000
bis-bromodealkylation with the formation of molecular
Abstract: Boron tribromide cleanly and quantitatively converts
borophosphonate oligomers [ O PR(O ) O B(O )
dimethyl-, diethyl-, diisopropyl-, and ditertiobutyl phosphonates
(O )]n.9 Removal of the volatile alkyl bromide ensures a
RP(O)(OR’)2 into the corresponding phosphonic acids RP(O)(OH)2
smooth and quantitative conversion. Subsequent metha-
nolysis at ambient temperature and removal in vacuo of
the solvents provided the free phosphonic acids 2a n in
high yield (Table). The formed B(OMe)3 was detectable
via methanolysis. The use of boron tribromide is compatible with a
variety of functionalities in the R group.
Key words: phosphorus, hydrolyses, protecting groups
11
in the B NMR spectrum ( = 18.6).10 Phosphonic acids
Phosphonic acids are conveniently prepared from the cor-
responding dialkyl esters by acid-catalyzed hydrolytic
dealkylation, by heating them with concentrated hydro-
chloric or hydrobromic acid for several hours.1 However
many multifunctional phosphonic esters are too delicate
to survive the harsh reaction conditions involved.
Rabinowitz has devised the use of chlorotrimethylsilane
to circumvent these vigorous acidic conditions.2
McKenna3 and others4 have reported the usefulness of
bromotrimethylsilane for the conversion of dialkyl phos-
phonates into the silyl esters thus making the correspond-
ing phosphonic acids readily available via hydrolysis with
neutral H2O.5 More recently, lanthanum ions have been
reported to catalyze the dealkylation of phosphonates.6
Table Selective Deprotection of Dialkyl Phosphonates with Boron
Tribromidea
Entry
Dialkyl
R
R’
Yield of 2c
Phosphonateb
1
2
1a
1b
1c
1d
1e
1f
Me
Me
Et
90
95
89
84
82d
92
77d
80d
92
94
89
82
87
89e
Et
3
Me
i-Pr
t-Bu
Et
4
Me
5
decyl
allyl
6
Me
Et
During the investigation on the preparation and reactions
of N-alkyl/aryl- - and -aminophosphonic acids7,8 based
on reductive alkylation of - and -azidophosphonates
with organodichloroboranes, it was noted that the trans-
formation was accompanied by simultaneous hydrolysis
of the phosphonates.8a In this communication, we show
that the most inexpensive boron tribromide is an extreme-
ly effective reagent for dealkylation of dialkyl phospho-
nates having different labile functional groups.
7
1g
1h
1i
benzyl
BrCH2CH2
NCCH2
8
Et
9
Et
10
11
12
13
14
1j
CH3(CH2)4COCH2 Et
1k
1l
HOCH2
Et
EtO2CCH2
MeSCH2
Et
1m
1n
Et
Me
a Phosphonates 1a−n and BBr3 were reacted in a 1:0.9 ratio (see Ex-
perimental Section).
The deblocking process of dialkyl phosphonates 1a n
was carried out with commercial BBr3 (1 M in hexane)
under mild and nonaqueous conditions. The addition of
boron tribromide to a solution of the dialkyl phosphonate
in anhydrous toluene under argon initially at 30 °C and
then at 70 °C led rapidly to the formation of insoluble oli-
gomers having isovalent P O B groups. The reaction
b All phosphonates are commercially available, except di-tert-butyl
methylphosphonate (1d) which was prepared from tri-tert-butyl
phosphite and iodomethane: Mark, V.; Van Wazer, J. R. J. Org.
Chem. 1964, 29, 1006.
c Isolated yields. The products were characterized by comparison
with authentic samples as the monoanilinium salt, unless otherwise
stated.
presumably proceeds via
a
primary adduct
d Isolated and recrystallized as the free phosphonic acid.
e Yield : 8.4 g, 0.035 mol scale.
Br3B•O=PR(OR’)2 which undergoes a thermally induced
Synthesis 2001, No. 4, 553–554 ISSN 0039-7881 © Thieme Stuttgart · New York

554
N. Gauvry, J. Mortier
SHORT PAPER
in toluene (15 mL) under argon at 30 °C and the the mixture was
stirred for 6 h at 70 °C. An excess of MeOH (10 mL) was added at
r.t. The solvents were removed in vacuo affording the crude phos-
phonic acid 2e which was recrystallized from hexane (0.365 g,
82%); mp 98 100 °C (Lit.12 mp 102 102.5 °C).
1H NMR (CD3OD, TMS): = 1.65 (m, 4 H, 2 CH2), 1.30 (m, 14 H,
7 CH2), 0.89 (m, 3 H, CH3).
2a n were either purified by recrystallization or isolated
as anilinium salts.5d
It was found that the ester cleavage is significantly influ-
enced by the ratio of the reagent to the substrate used.
Thus, treatment of diethyl ethylphosphonate (1b) with 0.6
equivalent of BBr3 gave a mixture of the unreacted 1b,
ethylphosphonic acid (2b), and monoethyl ethylphospho-
nate [EtP(O)(OEt)(OH)] (4:30:66). The reaction did not
reach to completion when 1.5 equivalents of boron tribro-
mide was used. The complete conversion of 1b into 2b
could be achieved with 0.9 equivalent of BBr3. Diisopro-
pyl and di-tert-butylalkyl phosphonates were also conve-
niently deprotected with the method (Table, entries 3 and
4).
13C NMR (CD3OD): = 32.0, 30.8 (JC-P = 16.5 Hz), 29.7, 29.6,
29.4, 29.3, 27.0 (JC-P = 137.5 Hz), 22.9 (JC-P = 5.4 Hz), 22.7, 13.5.
References
(1) Kosolapoff, G. M.; Maier, L. In Organic Phosphorus
Compounds, Wiley: New York, 1976, Vol. 7, p 9.
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M.-C. Tetrahedron Lett. 1977, 18, 155.
(b) McKenna, C. E.; Schmidhauser, J. J. Chem. Soc., Chem.
Commun. 1979, 739.
Analogous deprotections conducted with commercial bo-
ron tribromide in dichloromethane or complexed with
dimethyl sulfide gave similar results, whereas the reac-
tions of BCl3 resulted in the recovery of substantial
amounts of starting material.
(4) (a) Rudinskas, A. J.; Hullar, T. L.; Salvador, R. L. J. Org.
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In order to clarify the functional group selectivity, we ex-
amined competitive dealkylations of phosphonic esters
1f n having another labile functional group. The com-
pounds were treated with 0.9 equivalent of BBr3 in hexane
under standard conditions. In all cases the reaction pro-
ceeded to completion with essentially complete selectivi-
ty for P O dealkylation. Selective dealkylation of allyl-
(1f), benzyl- (1g), bromoethyl- (1h), cyanomethyl- (1i),
oxo-2-heptyl- (1j), hydroxymethyl- (1k), ethoxycarbon-
ylmethyl- (1l), methylthiomethyl- (1m), and phthalimi-
domethyl- (1n) phosphonates proceeded smoothly to give
the phosphonic acids 2f n in excellent yield (Table, En-
tries 6 14). It is noteworthy that the alternative method of
deprotection of phosphonates with trialkylsilyl halides is
ineffective when an allylic group is present in the R
group.11 The acids were characterized either directly or as
the monoanilinium salts (Table, entries 5, 7, and 8).
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The strikingly facile dealkylation of dialkyl phosphonates
by boron tribromide appears to constitute a truly mild pro-
cedure for the preparation of phosphonic acids, with par- (10) (a) Gerrard, W. Trans. J. Plastics Inst. 1967, 509.
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ticular promise for synthesis of phosphonic acids
incorporating sensitive functional groups, a category that
include compounds of biological interest.
Article Identifier:
Decylphosphonic Acid (2e); Typical Procedure
1437-210X,E;2001,0,04,0553,0554,ftx,en;P07500SS.pdf
BBr3 (1.8 mL, 1.8 mmol, 1 M in hexane) was added dropwise to a
stirred solution of diethyl decylphosphonate (1e; 0.556 g, 2.0 mmol)
Synthesis 2001, No. 4, 553–554 ISSN 0039-7881 © Thieme Stuttgart · New York