Application of tris(trimethylsilyl) phosphite as a convenient phosphorus nucleophile in the direct synthesis of tetrasubstituted αααα -aminophosphonic acids from ketimines

The condensation of tris(trimethylsilyl) phosphite with various ketimines leads directly to tetrasubstituted α - aminophosphonic acids. The presented reaction proceeds readily at room temperature and provides labile silylated esters of tetrasubstituted α -aminophosphonic acids, as non-isolable reaction intermediates. Subsequent methanolysis of the latter provides the desired α-aminophosphonic acids bearing an fully substituted α-carbon in good overall yields as crystalline non-hygroscopic solids after simple recrystallization from a methanol-acetone mixture.nordstom


Introduction
α-Aminophosphonic acids, as analogues of amino acids in which the carboxylic group is replaced by a phosphonic or related group (usually phosphonous or phosphinate) exhibit diverse biological properties and have found wide applications in many areas ranging from agriculture to medicine. 1 The interesting properties of α-aminophosphonic acids stem mainly from their structural analogy to natural carboxylic acids however equally important is the fact that the tetrahedral geometry of substituents around the phosphorus atom resembles the high-energy transition state of peptide bond hydrolysis. 2 The latter feature is directly responsible for the biological activity of these compounds, mostly as enzyme inhibitors.When searching for new enzyme inhibitors, the α-aminophosphonic acids are often incorporated in tailor-made peptide structures and those molecules are then tested for inhibitory activity.In that respect the use of tetrasubstituted αaminophosphonic acids as building blocks in the peptide synthesis is known to increase the rigidity of the peptide structure formed and thus improve its biological activity. 3The effective synthesis of tetrasubstituted α-aminophosphonic acids is therefore very important from the point of view of the design and preparation of new and more active pharmaceuticals.
The most common protocol for the synthesis of α-aminophosphonates relies upon the formation of the C-P bond via addition of phosphorus nucleophile to carbon-nitrogen double bond (C=N) in imines or ketimines.In the case of the preparation of α-aminophosphonates bearing an all-substituted α-carbon however, this protocol is difficult to perform due to the poor electrophilic character of the carbon atom in the corresponding ketimines and the additional steric hindrance present at the reaction center.Because of that, the reaction usually requires prolonged heating of the reagents in a high boiling point solvent or requires the presence of additional reagents / catalysts to go to completion. 4,5Additionally, in order to obtain the tetrasubstituted αaminophosphonic acids, an additional synthetic step is required, namely, the hydrolysis of αaminophosphonates, which is usually performed again by prolonged heating of the substrate in the presence of a strong mineral acid, such as HCl.Therefore in order to synthesize thermally unstable and delicate αaminophosphonates and phosphonic acids bearing an fully substituted α-carbon such as e.g.heterocyclic derivatives, there is a need to replace the harsh reaction conditions with a milder protocol.][8] As a part of our continuing interest in organophosphorus chemistry [9][10][11][12] and particularly in the synthesis of new α-functionalized phosphonates and corresponding phosphonic acids [13][14][15][16][17][18] we decided to embark on a project aiming at development of an effective and mild protocol for the synthesis of tetrasubstituted αaminophosphonic acids.We report herein the addition of tris(trimethylsilyl) phosphite to various N-benzyl ketimines as a very useful direct method, which affords desired α-aminophosphonic acids with good overall yields and under mild reaction conditions.7][8] In turn, to demonstrate the versatility of the method we also applied it to ketimines derived from aliphatic ketones.Importantly, the use of benzylamine for the synthesis of ketimines allowed us to easily deprotect the amine function by hydrogenolysis, yielding the tetrasubstituted α-aminophosphonic acids with a free amine group ready for use in e.g.peptide synthesis.

Results and Discussion
We began our studies with the preparation of appropriate ketimines.This was done by heating the ketones (aliphatic or heteroaromatic) with benzylamine in toluene at reflux (110 o C) in a Dean-Stark apparatus for 3 h.After that time the solvent was removed on vacuum yielding the desired ketimines, which were used in the next step without further purification.Subsequently, the ketimines 1a-f were subjected for reaction with tris(trimethylsilyl) phosphite in dichloromethane at room temperature (Table 1).This reagent was conveniently prepared in situ by reaction of commercially available trimethyl phosphite (P(OMe) 3 ) with bromotrimethylsilane (BrSiMe 3 ) in a molar ratio 1:4, in dichloromethane at room temperature. 19,20Reaction of tris(trimethylsilyl) phosphite with ketimines 1a-f produced, in the first stage, the corresponding labile silylated esters of tetrasubstituted α-aminophosphonic acids 2a-f as reaction intermediates which were not isolated but, in the second step, were treated with methanol, as dealkylating (desilylating) agent, producing the desired crude α-aminophosphonic acids 3a-f (Table 1).Analytically pure samples of the αaminophosphonic acids 3a-f were obtained after simple recrystallization from methanol-acetone mixture.
Table 1.Reaction of ketimines 1a-f with tris(trimethylsilyl) phosphite The described above method presents a substantial improvement in the direct synthesis of αaminophosphonic acids bearing a fully substituted α-carbon, especially derivatives containing fragile moieties such as heterocyclic systems.The in situ generated tris(trimethylsilyl) phosphite was found to be a good nucleophile toward the ketimines.The presence of a bulky trimethylsilyl group in the formed phosphonate or phosphonite-like ester increases the power of such a nucleophile due to formation of a stable, threecoordinated phosphorus moiety with a free electron pair at phosphorus.Also, absence of the possibility for tautomerization in the formed three-coordinated, silylated phosphorus ester into less nucleophilic fourcoordinated phosphonate-like ester, additionally secure the nucleophilic character of the applied reagent.Application of this nucleophile in the present case of the direct synthesis of the tetrasubstituted αaminophosphonic acids enabled the reaction to proceed readily at room temperature and produced the desired products in good overall yields.It has to be noted, that the heterocyclic derivatives synthesised here, © ARKAT USA, Inc containing of pyridine 3c-g and thiophene 3h units, are reported for the first time.
In order to obtain the target α-aminophosphonic acids with a free amino group, as potentially useful building blocks for application in e.g.peptide synthesis, we decided to assess the deprotection of obtained Nbenzyl derivatives of phosphonic products on the representative example of 3c.Due to the presence of a benzyl group in the labile heterocyclic products, the deprotection of the amine could be carried out under very mild conditions (Pd/C (10 mol%), 1 eq.HCl (38% aq.), H 2 ).A sample of α-aminophosphonic acid 3c was dissolved in methanol and then Pd/C (10 mol%) was added followed by addition of 1 eq. of HCl (38 % aq.solution).The resulting reaction mixture was vigorously stirred for 3 h under a hydrogen atmosphere.After filtration of the reaction mixture through the Celite the desired free α-aminophosphonic acid 4 was obtained in 85% yield by evaporation of the filtrate and recrystallization of the crude product from ethanol-diethyl ether mixture (Scheme 1).Scheme 1. Synthesis of 2-pyridyl-containing tetrasubstituted α-aminophosphonic acids 4 by hydrogenolysis of N-benzyl derivative 3c.

Conclusions
We have reported above a very mild and effective protocol for the synthesis of tetrasubstituted αaminophosphonic acids by means of nucleophilic addition of tris(trimethylsilyl) phosphite, generated in situ, as a very reactive phosphorus nucleophile, to ketimines derived from benzylamine and various ketones.The reactions proceeded at room temperature and produced, in the first stage, the corresponding silylated esters of tetrasubstituted α-aminophosphonic acids, which after treatment with methanol underwent desilylation and transformation into the desired α-aminophosphonic acids with good overall yields.Additionally, the use of benzylamine in the described protocol allowed us to easily deprotect the amine functionality and obtain the target α-aminophosphonic acids with a free amino group, that may be of interest as building blocks for e.g.peptide synthesis and the preparation of new enzyme inhibitors.