Regioselective ester cleavage during the preparation of bisphosphonate methacrylate monomers

Article abstract of DOI:10.3762/bjoc.7.46

New functional monomers bearing a methacrylate, a bisphosphonate function and, for most, an internal carboxylate group, were prepared for incorporation into copolymers with adhesive or anticorrosive properties. Methanolysis of some trimethylsilyl bisphos-phonate esters not only deprotects the desired bisphosphonate function but also regioselectively cleaves the alkyl ester function without affecting the methacrylate ester.

Full text of DOI:10.3762/bjoc.7.46

Regioselective ester cleavage during the preparation
of bisphosphonate methacrylate monomers
Kamel Chougrani, Gilles Niel, Bernard Boutevin and Ghislain David*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 364–368.
Institut Charles Gerhardt, UMR 5253 CNRS, Ecole Nationale
Supérieure de Chimie, 8, rue de l'Ecole Normale, 34296 Montpellier
Cedex 5, France
doi:10.3762/bjoc.7.46
Received: 28 January 2011
Accepted: 08 March 2011
Published: 25 March 2011
Email:
Ghislain David* - ghislain.david@enscm.fr
Associate Editor: H. Ritter
* Corresponding author
© 2011 Chougrani et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
bifunctional monomer; phosphonic acid; regioselective ester cleavage
Abstract
New functional monomers bearing a methacrylate, a bisphosphonate function and, for most, an internal carboxylate group, were
prepared for incorporation into copolymers with adhesive or anticorrosive properties. Methanolysis of some trimethylsilyl bisphos-
phonate esters not only deprotects the desired bisphosphonate function but also regioselectively cleaves the alkyl ester function
without affecting the methacrylate ester.
Introduction
The potential applications for polymer products containing pounds [10-17], however, there has been very little investi-
phosphorus are numerous; dental adhesives, ion-exchange gation into the use of phosphonate-type methacrylates for the
resins and adhesion promotors are just three of the more same purpose [8,9]. In the domain of polymer-based materials
common applications [1-7]. Compounds containing phospho- exhibiting specific properties, bifunctional monomers bearing a
rous are excellent promotors with respect to adhesion, and thus methacrylate function and a bisphosphonate function are recog-
anti-corrosion. Commercial anti-corrosion polymer compounds nized as useful building blocks for dental materials
are generally formed from Sipomer® or Phosmer® monomers, [11,12,18,19]. Such materials require a high hydrolytical
which are phosphate-type (meth)acrylates, and can be readily stability that originates in the hydrolytical stability of the
polymerized by emulsion or solution methods [8,9]. Polymers monomers. With this requirement in mind, we have investi-
with some phosphonate functionality have long been gated the synthesis of bisphosphonates and their deprotection to
established as excellent adhesives and anti-corrosion com- the corresponding acids.
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Beilstein J. Org. Chem. 2011, 7, 364–368.
Results and Discussion
Synthesis of bisphosphonate methacrylate
monomers
We have designed new bifunctional monomers 1a–7a bearing a
methacrylate and an amino(bismethylene)bisphosphonate
(Scheme 1) linked by an aliphatic or an aromatic spacer [20,21].
esterified with (hydroxyethyl)methacrylate (HEMA, 22) to give
the monomers 4c and 5c. The two aromatic targets 6c and 7c
were prepared from p-(aminomethyl)benzoic acid (17) which
was converted into the bisphosphonate 18 in 92% yield under
Kabachnik–Fields conditions. This common intermediate 18
was either reduced by diborane to the alcohol 19 followed by
esterification by methacryloyl chloride giving access to com-
To the best of our knowledge, only a single acrylate containing pound 6c, or esterified directly with HEMA (22) to furnish the
monomer 8 has been previously synthesized and tested, after bisphosphonate 7c.
copolymerization and incorporation, in a desensitizing solution
Study of bisphosphonate methacrylate mono-
for lithography [22]. More recently we investigated a similar
compound 1a for its adhesive or anticorrosive or flame-retar- mer deprotection
dant properties [20,21]. The synthesis of bisphosphonate As already mentioned in the introduction, the resulting poly-
monomers 1c–7c is described in Scheme 2.
mers from bisphosphonate methacrylate monomers can be
involved in many applications such as dental adhesives, ion-
Thus bisphosphonate 1c was simply obtained from exchange resins and adhesion promotors. However, these poly-
2-aminoethanol (9) by a two-step process involving first mers must be in the acidic form, i.e., with phosphonic acid
Kabachnik–Fields conditions [23,24] to introduce the bisphos- groups, to function efficiently [26].
phonate moiety followed by esterification of compound 10 with
methacryloyl chloride. The synthesis of the next aliphatic target The intermediate bisphosphonates were then subjected to a two-
molecules 2c–4c and 3c–5c started from 6-aminohexanoic acid step deprotection process to restore the phosphonic acids by
(11) and 11-aminoundecanoic acid (12), respectively. The three using first trimethylsilyl bromide followed by a methanolysis
component coupling of 11, respectively 12, with paraformalde- step [27]. The first step is known to transform alkyl phospho-
hyde and dimethyl phosphite furnished bisphosphonates 13 and nates into the corresponding trimethylsilyl phosphonates which
14 in excellent yields. These latter compounds were then are then cleaved to the phosphonic acids under hydrolytic
reduced regioselectively by diborane [25] to the corresponding conditions [28]. Phosphonates 1c–7c were treated with
alcohols 15 and 16, respectively. Their subsequent esterifica- trimethylsilyl bromide for 16 h at room temperature to give the
tion in the presence of methacryloyl chloride gave the target trimethylsilyl esters 1b–7b which were isolated in quantitative
molecules 2c and 3c. Alternatively, compounds 13 and 14 were yields (Scheme 3).
Scheme 1: Novel bisphosphonate methacrylate monomers.
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Beilstein J. Org. Chem. 2011, 7, 364–368.
Scheme 2: Synthesis of novel bisphosphonate methacrylate monomers 1c–7c, by use of the following reagents and conditions: (a) paraformalde-
hyde, (MeO)2P-OH, THF, reflux, 96%; (b) methacryloyl chloride, NEt3, CHCl3, 68%; (c) paraformaldehyde, (MeO)2P-OH, THF, reflux (n = 5, 92%; n =
10, 95%); (d) BH3-THF, CH2Cl2 (n = 5, 87%; n = 10, 85%); (e) methacryloyl chloride, NEt3, CHCl3 (n = 5, 75%; n = 10, 77%; (f) HEMA (22), DCCI,
DMAP, CHCl3 (n = 5, 74%; n = 10, 73%); (g) paraformaldehyde, (MeO)2P-OH, THF, reflux, 92%; (h) B2H6; (i) methacryloyl chloride, NEt3, CHCl3,
62%; (j) HEMA (22), DCCI, DMAP, CHCl3, 65%.
Scheme 3: Schematic procedure for phosphonate methacrylate monomer deprotection.
1H NMR analysis of compounds 1b–7b showed the absence of The crude silyl esters 1b–7b were dissolved in methanol and
deprotected products 1a–7a which could have arisen from stirred for 2 h at ambient temperature. Concentration of the
possible traces of residual HBr. The next challenge was to reaction mixture furnished phosphonic acids 1a–3a and 6a, 7a
cleave the trimethylsilyl phosphonates selectively, without in good yields (Table 1, entries 1 and 2) while methanolysis of
affecting alkyl carboxylates, under controlled conditions of both compounds 4b and 5b resulted in a mixture of the desired phos-
temperature and solvent [23] since alkyl esters including acry- phonic acids 4a and 5a, HEMA (22) and the phosphonic acids
late or methacrylate esters are sensitive to hydrolytic conditions 20 and 21, respectively (entries 4 and 5). In both the latter cases
[29]. According to McKenna's recent results, the use of careful 1H NMR examination of the reaction mixture from the
methanol instead of water should achieve the selective depro- methanolysis step revealed that the phosphonic acid 4a, respect-
tection of these trimethylsilyl phosphonates [30]. Our results are ively 5a, was the sole compound until evaporation of the
summarized in Table 1.
solvent. These results showed that the internal carboxylic ester
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Beilstein J. Org. Chem. 2011, 7, 364–368.
concentrating the reaction mixture leading to increasing propor-
tions of HEMA (22), respectively HBMA (23) as the molar
percentage of hydroxymethylphosphonic acid increases. These
last results are in agreement with the observed cleavage of com-
pounds 4a and 5a and show the weak influence of the chain
length between the methacrylate and acetate groups. It is worth
mentioning that the phosphonic acid 7a is stable in the two-step
deprotection process (Table 1, entry 7) emphasizing the greater
stability of conjugated carboxylic esters over unconjugated
ones.
Table 1: Deprotection of phosphonates 1b–7b obtained with the
following conditions: 1) TMSBr, CHCl3, RT, 16 h; 2) MeOH, RT, 2 h.
Entry
Reactant
Product
Yield (%)a
1
2
3
4
5
6
7
1b
2b
3b
4b
5b
6b
7b
1a
2a
95
97
3a
94
97 (30/35/35)b
98 (30/35/35)b
98
4a/9/24
5a/9/25
6a
Other examples of similar phosphonate deprotection by TMSBr
involved the presence of a tertiary amine but the authors did not
mention any cleavage of the carboxylic ester to prove the role
of the base used during the selective deprotection of the phos-
phonic ester into its acid [32]. We finally deprotected the
trimethylsilyl phosphonates 4b and 5b with methanol in the
presence of aqueous ammonia (reaction time 1 h) to obtain the
7a
99
aCrude yield after solvent evaporation. bRelative proportions as deter-
mined by 1H NMR.
was only cleaved after concentration of the reaction mixture target phosphonic acids 4a and 5a in quantitative yields as their
probably due to the higher acidity of the medium and are in ammonium salts.
agreement with the previously described deprotections using
water as solvent [31].
Conclusion
In conclusion we were able to prepare new bifunctional
We prepared two model compounds 24 and 25 derived from monomers bearing a methacrylate function and a bisphos-
acetylation of HEMA (22) and (hydroxybutyl)methacrylic acid phonic acid function. We confirmed that the unconjugated alkyl
(HBMA, 23), respectively to study the deprotection of these ester function involved in these monomers was cleaved selec-
esters in the methanol under increasing concentrations of tively in the presence of conjugated esters by the released phos-
hydroxymethylphosphonic acid as a model phosphonic acid. phonic acid. The use of methanol instead of water during this
Our results are summarized in Table 2.
final deprotection step was essential to preserve the more stable
methacrylate and benzoate esters.
We observed that: i) Both ester functions were stable until evap-
oration of the mixture, ii) the sole acetyl group was cleaved by
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