A convenient and general procedure for the synthesis of α-ureidophosphonates under catalyst-free conditions

We report here a novel and convenient method for the synthesis of α-ureidophosphonates through a one-pot reaction of three component condensation of aldehyde with urea and diethylphosphite under catalyst-free conditions in toluene at reflux. Treatment of aldeyhde with a mixture of urea and diethylphosphite gives a α-ureidophosphonate in moderate yield. The α-ureidophosphonate product was easily separated and crystallized from the reaction mixture.


Introduction
The organic chemistry of phosphorus compounds have became increasingly useful and important in organic synthesis.Among the organophosphorus compounds, phosphonic acids are important class of compounds that exhibit a variety of interesting and useful properties. 1 The synthesis of α-substituted phosphoryl derivatives (phosphonic and phosphinic acids) has attracted significant attention due to their biological activities with broad application as enzyme inhibitors, antimetabolites and antibiotics. 2Among α-functionalized phosphonic acids, αaminoalkylphosphonic derivatives have biological activities such as anti-bacterial, 3 herbicidal 4 and fungicidal. 5Aminoalkylphosphonic acids, the phosphonic acid analogues of 1-amino carboxylic acids, are important class of compounds that exhibit a variety of interesting and useful properties. 6While the synthesis and properties of many types of aminophosphonic acid derivatives have been widely investigated, [7][8][9] studies of α-ureidophosphonates have received little attention.α-Ureidophosphonates have been used as precursor for the synthesis of chiral 1aminophosphonates. 10α-Ureidophosphonates have shown moderate activity against number of fungal pathogens. 11They also display powerful antiviral activities against TMV. 12 Besides their biological importance, α-ureidophosphonates are also known for their metal chelating ability. 13n addition, these compounds used as active ingredients in pesticides especially insecticides and acaricides. 14n contrast to extensive studies on the synthesis of 1-aminophosphonic acid derivatives, 15 relatively few papers have been reported on the synthesis of α-ureidophosphonates. Synthetic routes to -ureidophosphonates involve prolonged heating of three component reaction of trialkylphosphite with urea and aldehydes at 50 °C in the presence of BF3 as a catalyst under nitrogen described by Birum, 16 and the reaction of aminophosphonates with isocyanates in the presence of LDA at -30°C. 17However there are some problems associated with these methods including harsh reaction conditions, long reaction times and side reactions.On the other hand, three component reaction of trialkylphosphite with urea and aldehydes at 50 °C in the presence of BF3 as a catalyst under nitrogen, gave urylenediphosphonates as major product.In this method the formation of urea monophosphonates (α-ureidophosphonates) is accompanied by the formation of urylenediphosphonates, even when equimolar quantities of reactants was used and pure α-ureidophosphonates are difficult to isolate.As part of our efforts to explore the novel methods for the synthesis of organophosphorus compounds, 18 we report a new method for the synthesis of α-ureidophosphonates from the one-pot three component condensation of aldehyde with urea and diethylphosphite under catalyst-free conditions in toluene at reflux.

Results and Discussion
Treatment of p-chlorobenzaldehyde (1a), as a model compound, with a mixture of urea and diethylphosphite was studied in toluene, and the progress of the reaction was monitored by TLC.Treatment of 1a with urea in the presence of diethylphosphite in dry toluene at room temperature failed after 24 h to form any product.When the reaction was carried out at reflux for 7 h, a mixture of products was obtained (Scheme 1).The 31 P-NMR spectrum of this mixture exhibited three peaks at  22.53, 22.82 and 23.11 ppm due to the mixture of two diastereoisomers 3a (in a 63:37 ratio of diastereoisomers, Scheme 1) and diethyl α-ureido(4-chlorophenyl)methylphosphonate 2a.
When the reaction mixture was subjected to washing with water, and evaporation of the solvent, only 2a crystallized from a mixture of diethyl ether and n-hexane.The structure of 2a was confirmed by NMR data and X-ray analysis.In the 31 P-NMR spectrum, a singlet peak appeared at  22.50 ppm.The 1 H-NMR spectrum had a doublet of doublets peak at 5.40 ppm (JHP 22 Hz and JHH 10 Hz) which corresponds with the hydrogen -CH-in the product 2a (simplified from doublet of doublets to doublet by addition of D2O).The 13  The structure was supported by its X-ray analysis.We could obtain suitable crystals for 2a for X-ray analysis.The crystal structure of 2a is illustrated in Figure 1.This process was successfully applied to other aldehydes 1 as summarized in Table 1.As shown in Table 1, the reaction of different substituted (ortho, meta and para)-of benzaldehydes with a mixture of urea and diethylphosphite in dry toluene at reflux, afforded the corresponding α-ureidophosphonates derivatives 2 in 30-54 % isolated yields (entries 1-10).Treatment of benzaldehyde and thiophene-2-carbaldehyde with a mixture of urea and diethylphosphite in toluene at reflux, gave corresponding urylenediphosphonate 3k and 3l as major product (entries 11 and 12).When the reaction mixture of benzaldehyde and thiophene-2-carbaldehyde was subjected to washing with water followed by adding a mixture of solvents diethyl ether and n-hexane, corresponding α-ureidophosphonates (2k and 2l) did not crystallize from the reaction mixture.The reaction of heptanal, as an aliphatic aldehyde, with a mixture of urea and diethylphosphite in toluene at reflux, afforded an unknown mixture (entry 13).
Birum reported three component reaction of trialkylphosphite with urea and aldehyde at 50 °C in the presence of BF3 as a catalyst under nitrogen, but this method gave urylenediphosphonates as major product.16a In this catalytic method, three component reaction of trialkylphosphite with thiourea and aldehydes at 50 °C in the presence of BF3 as a catalyst under nitrogen, failed to give the corresponding adduct.16a We were interested to examine the three component reaction of dialkylphosphite with thiourea and 4-chlorobenzaldehyde (1a) in toluene at reflux.Treatment of 1a with thiourea in the presence of diethylphosphite in dry toluene at room temperature failed after 24 h to form any product.When the reaction was carried out at reflux for 7 h, gave corresponding α-thioureidophosphonate 4a in 48 % isolated yield (Scheme 2).

Conclusions
We have developed a simple and practical approach for the synthesis of α-ureidophosphonates. Through a three component reaction of aldehydes with a mixture of urea and diethylphosphite under catalyst-free conditions in toluene at reflux, α-ureidophosphonates can be synthesized cleanly in moderate yield.The structure of α-ureidophosphonates was determined by NMR data and X-ray analysis. 20Treatment of aldehydes with thiourea in the presence of diethylphosphite in dry toluene at reflux for 7 h, gave corresponding α-thioureidophosphonate in moderate isolated yield.Some of the major advantages of this protocol are: simple procedure, easy work-up, and catalyst-free conditions.

Synthesis of α-ureidophosphonates (2).
The aldehyde (10 mmol) was added to a stirred mixture of urea (1 g, 3.07 mmol) and diethylphosphite (10 mmol) in dry toluene (50 mL) at reflux and the solution was stirred for 7-14 h.Stirring was continued for 1 h at room temperature and then the reaction mixture was washed with water (3x50 mL) and the solvent was removed under vacuum.A mixture of 50:50 diethyl ether/n-hexane (50 mL) was added to the reaction mixture and pure product 2 was crystallized from the mixture.All products gave satisfactory spectral data in accord with the assigned structures.

Table 1 .
Synthesis of α-ureidophosphonates via one-pot three component condensation of aldehyde, urea and diethylphosphite b Unknown mixture.