Microwave-assisted synthesis of (aminomethylene)bisphosphine oxides and (aminomethylene)bisphosphonates by a three-component condensation

A practical method was elaborated for the synthesis of (aminomethylene)bisphosphine oxides comprising the catalyst- and solvent-free microwave-assisted three-component condensation of primary amines, triethyl orthoformate and two equivalents of diphenylphosphine oxide. The method is also suitable for the preparation of (aminomethylene)bisphosphonates using (MeO)2P(O)H/(MeO)3CH or (EtO)2P(O)H/(EtO)3CH reactant pairs and even secondary amines. Several intermediates referring to the reaction mechanism together with a few by-products could also be identified.


Introduction
Substituted (hydroxymethylene)bisphosphonic acid derivatives form an important group of drugs used in the treatment of osteoporosis and related bone diseases [1][2][3].In the last decades, at least three generations of dronic acid derivatives appeared [4].
(Aminomethylene)bisphosphonic acid derivatives are analogous species, that also have potential bioactivity in bone diseases, besides they display antibacterial, antiparasitic, anticancer and herbicidal activities [5].
(Aminomethylene)bisphosphonates may be prepared in different ways [5].One of the most convenient and widespread methods is the three-component condensation involving an amine, an orthoformate and a dialkyl phosphite.Usually, primary or secondary amines were reacted with an equivalent, Scheme 1: Proposed routes for the three-component condensation [7].
The mechanism of the three-component condensation has been investigated by the research group of Krutikov and Kafarski [6,7].A detailed proposal is shown in Scheme 1 [7].The first step of the condensation is the reaction of the amine with the orthoformate, in which imine-type intermediates I or II may be formed.The next step is the nucleophilic addition of diethyl phosphite to the C=N bond of the imines resulting in phosphonates III or IV, respectively.Then, the elimination of an amine or ethanol and the addition of another unit of diethyl phosphite may lead to (aminomethylene)bisphosphonates (VI).If the amine is in predominance over the phosphite in the reaction, the pathway A is more likely, but if the phosphite is used in excess, the pathway B comes to the fore.
There are other possibilities to synthesize (aminomethylene)bisphosphonates, such as by the reaction of dimethylformamide diethyl acetal with diethyl phosphite (Scheme 2a) [33], by the condensation of formamides and diethyl phosphite using 2,6-ditert-butyl-4-methylpyridine (DTBMP) as the base, and trifluoromethanesulfonic anhydride (Tf 2 O) as the catalyst (Scheme 2b) [34], or by the reaction of isonitriles with triethyl phosphite (Scheme 2c) [35,36].(Aminomethylene)bisphosphonates can also be obtained starting from amides, triethyl phosphite and phosphorus oxychloride (Scheme 3a) [37], or in the reaction of amines with diazophosphonate in the presence of a rhodium catalyst (Scheme 3b) [38].(Aminomethylene)bisphosphine oxides are analogous to (aminomethylene)bisphosphonates, but they are much less studied.Only a few publications were found, which focus on their synthesis [33,[39][40][41][42], however, a three-component condensation has not been described.They can also be prepared starting from dimethylformamide dimethyl acetal, as in the synthesis of (aminomethylene)bisphosphonates, but in the latter case a secondary phosphine oxide is the P-reagent [33,39].In addition, (aminomethylene)bisphosphine oxides can be synthe- sized by the reaction of two molecules of (dialkylamino)(diphenylphosphinoyl)chloromethane (Scheme 4a) [40,41], or by the addition of diphenylphosphine oxide to an isonitrile (Scheme 4b) [36,42].In this paper, we wish to report the results of our investigations on the synthetic protocol utilizing the three-component condensations of primary or secondary amines, orthoformates and >P(O)H species, such as dialkyl phosphites or diphenylphos-phine oxide, and we aimed at the preparation of new derivatives.

Synthesis of alkylamino-and (phenylaminomethylene)bisphosphine oxides
In the first series of experiments, the condensation of primary amines, such as butyl-, cyclohexyl-and benzylamine or aniline with triethyl orthoformate, and 2 equivalents of diphenylphosphine oxide at 150 °C for 1 h under MW conditions was studied (Scheme 5).To avoid the formation of by-products, benzylamine was reacted at a lower temperature of 125 °C (Table 1, entry 3).The reactions were carried out without any catalyst and solvent.After column chromatography, the new aminomethylenebisphosphine oxides 1a-d were obtained in yields of 72-82% (Table 1, entries 1-4).The condensation of simple secondary amines (diethyl-, dibutyl-, N-butylmethyl-, N-cyclohexylmethyl-, N-benzylmethylamine, N-methylaniline and morpholine) was also investigated with triethyl orthoformate, and 2 equivalents of diphenylphosphine oxide (Scheme 6, Table 2).The MW-assisted reactions were performed at 150 °C for 1 h under solvent-and catalyst-free conditions, and the (dialkyl-aminomethylene)bisphosphine oxides 2a-g were obtained in yields of 60-85% after column chromatography (Table 2, entries 1-7).Except for compound 2g, all (aminomethylene)bisphosphine oxides (2a-f) prepared are new compounds.According to the literature method [41], 2g was synthesized by the reaction of two molecules of (diphenylphosphinoyl)morpholinochloromethane in the presence of chloroform at 5 °C for 18 h in a yield of 41% (Scheme 4a).Using the MW-assisted threecomponent condensation method, this compound (2g) can be synthesized without any catalyst and solvent in a short time (1 h), and in a yield of 85% (Table 2, entry 7).

Synthesis of alkylamino-and (phenylaminomethylene)bisphosphonates
In the next stage, our method was extended to the synthesis of alkyl-and (phenylaminomethylene)bisphosphonates by reacting butyl-and cyclohexylamine or aniline, and triethyl orthoformate with diethyl phosphite under MW irradiation in the absence of catalyst and solvent (Table 3).First, the condensa-tion of butylamine, triethyl orthoformate with 2 equivalents of diethyl phosphite was studied at 125 °C.After a 2 h's reaction time, the conversion was 91%, and beside the expected (aminomethylene)bisphosphonate 3a formed in 81%, the N-ethylated by-product 4a was formed in 19% (Table 3, entry 1).Increasing the temperature to 150 °C, the reaction was completed after 30 min, but the proportion of the main product 3a was somewhat lower (78%), and another by-product 5a also appeared in 7% (Table 3, entry 2).The target compound 3a could be obtained in a yield of 61%.Using 3.5 equivalents of diethyl phosphite at 125 °C for 1 h, the conversion was only 75%, but the expected product 3a was formed exclusively (Table 3, entry 3).After a longer reaction time of 1.5 h, by-product 4a also appeared in 22% (Table 3, entry 4).In the reaction with cyclohexylamine, the same tendency was observed (Table 3, entries 5-8), and the corresponding (cyclohexylaminomethylene)bisphosphonate 3b was obtained in a yield of 68% after column chromatography (Table 3, entry 6).Finally, the three-component condensation of aniline, triethyl orthoformate and diethyl phosphite was studied (Table 3, entries 9-11).Applying 2 equivalents of phosphite, the reaction was not complete, neither at 125 °C, nor at 150 °C (Table 3, entries 9 and 10).Two types of imine intermediates (6a and 6b) could be observed in the reaction mixture beside the expected product 3c.These intermediates refer to the mechanism of the condensation (see compounds I and V in Scheme 1, pathway A).Previously, iminephosphonate 6b was only an assumed intermediate [7], but now we could prove it by 31 P NMR and HRMS (Table 4).Increasing the amount of diethyl phosphite to 3 equivalents, the reaction was complete at 125 °C after 1 h, and only 3c was formed with a yield of 82% (Table 3, entry 11).In the cases discussed, no ethylated or formylated by-products (4 and 5, respectively) were formed.(Aminomethylene)bisphosphonates 3b and 3c were synthesized earlier in unoptimized experiments to provide compounds 3b and 3c in yields of 36% [9] and 53% [8], respectively.The former compound 3b was characterized only by 1 H NMR [9].Compound 3c was also synthesized under MW irradiation in a yield of 75% [31].It can be seen, that the refined MW-assisted method elaborated by us a On the basis of GC (entries 1-8) or on the basis of HPLC (entries 9-11).b The by-products identified: c Isolated yield.d The following intermediates were also formed based on LC-MS: may give the (aminomethylene)bisphosphonates 3b and 3c in yields of 68% and 82%, respectively.
Next, the condensation of aniline with trimethyl orthoformate and dimethyl phosphite was also performed (Scheme 7).In this case, the reaction was complete after a 1 h heating at 110 °C using 3.5 equivalents of dimethyl phosphite.After column chromatography, the corresponding product 7a was isolated in a yield of 63%.At higher temperatures, decomposition was observed.
In the next stage, the MW-assisted reaction of secondary amines was studied with triethyl orthoformate and diethyl phosphite (Scheme 8).The condensations were carried out applying 3.5 equivalents of diethyl phosphite at 125 °C for 1 h in the absence of a catalyst and a solvent.In case of N-methylaniline, 4.5 equivalents of the P-reagent was necessary to attain complete conversion (Table 5, entry 6).The corresponding (dialkylaminomethylene)bisphosphonates (8a-g) were obtained in yields of 65-86% after purification by chromatography (Table 5, entries 1-7).
The composition of the reaction mixture for the experiment marked by Table 6, entry 6 was analyzed by 31 P NMR (see Figure 3).It was observed that increasing the quantity of dialkyl phosphite, the proportion of the by-products was decreased, and the condensations became more selective for the desired product (7a or 7b) (Table 6, Figure 1).In the reaction with dimethyl phosphite, the best result was achieved using 20 equivalents of the P-reagent, but in case of dibutyl phosphite, a 15-fold excess was sufficient (Table 6, entries 5 and 10).a On the basis of GC (entries 1-5) or on the basis of HPLC (entries 6-9).b The product composition has not changed using a larger excess of dialkyl phosphite.
Figure 1: Effect of the quantity of dimethyl phosphite (DMP) on the product composition (from Table 6, entries 1-5.)

Conclusion
In summary, we have developed a facile, solvent-and catalystfree MW-assisted method for the synthesis of (aminomethylene)bisphosphine oxides (AMBPOs) and (aminomethylene)bisphosphonates by the condensation of a primary or secondary amine, an orthoformate, and diphenylphosphine oxide or a dialkyl phosphite.This method is a novel approach for the preparation of AMBPOs and an optimized process for the synthesis of (aminomethylene)bisphosphonates.Twentytwo derivatives were isolated and characterized, except two, all of them are new compounds.Furthermore, a few intermediates supporting the mechanism of the condensation, and several by-products were also identified.

Supporting Information
Experimental procedures, characterization data, details of the NMR structural determination of all products and copies of 31 P, 1 H, and 13 C NMR spectra for all compounds synthesized are presented in Supporting Information File 1.
a Isolated yield.

Table 3 :
The reactions of primary amines with triethyl orthoformate and diethyl phosphite.