An effective catalyst-free microwave-assisted synthesis of a-aminophosphonates from ketones in a three-component system was shown. The method affords a-aminophosphonates in high yields from various ketones including natural porphyrine derivatives.

S y n t h e s i s o f a -A m i n o P h o s p h o n a t e s D e r i v e d f r o m F o r m y l p o r p h y r i n sAbstract: The first synthesis of a-amino phosphonates comprising porphyrin core was accomplished. Three methods of obtaining aamino phosphonates 5-8 were compared. Conventional heating of formylporphyrins 1-4 with t-BuNH 2 and (EtO) 2 P(O)H in various solvents was ultimately unsuccessful for preparing 5-8 whereas the use of microwave irradiation made it possible to obtain 5-8 in good yields. Regioselective preparation of 5-8 in excellent yields was achieved by combining microwave-assisting conditions and catalysis with CdI 2 . Efficient synthetic procedures of obtaining formylporphyrins 3,4 in large scale were also proposed.Extensive substituent manipulations on porphyrins derived from naturally occurring tetrapyrroles (e.g. heme and chlorocruoroheme) produce a number of phototherapeutic agents efficiently utilized in diverse medical fields including ophthalmology, oncology, gynecology, dermatology, urology, cardiology and immunology. 1-4 The method allowing tetrapyrroles to be used as photosensitizers (PSs) is called photodynamic therapy (PDT). Due to the basic concept of PDT, the combination of two therapeutic agents, a PS and light, which have low toxicity by themselves and being combined in the presence of oxygen lead to ultimate tissue destruction. [1][2][3][4] In order to construct porphyrin-based PSs capable of accumulating selectively in neoplastic (e.g. tumor) tissues a variety of synthetic approaches were elaborated. 1,2 Promising results were achieved by introducing pharmacophor units (e.g. alkoxy-, amino-, a-amino acid residues) into the side-chain positions of porphyrins. 1,2,5 An intriguing class of biologically active compounds are a-amino phosphonates. Due to their structural analogy with a-amino acids and transition state mimicking of peptides, a-amino phosphonates act as potent antibiotics, 6 peptide mimics, 6,7 enzyme inhibitors 6,8 and pharmacological agents. 9With the aim of combining in one molecule phototherapeutic potential of porphyrins and unique biological activity of a-amino phosphonates, we report the first synthesis of a-amino phosphonates comprising porphyrin moiety. It is well documented 10-14 that heterocyclic a-amino phosphonates could be efficiently prepared by the addition of phosphites to aldimine, generated from the corresponding amines and heterocyclic aldehydes. Although there is a broad variety of formylporphyrins derived from natural tetrapyrrols, 2,15 we chose to utilize namely 1-4 15,16 as aldehyde components since formyl group of 1-4 was reported to be an optimum site for designing potent pharmacological agents. 1,2,17-20 (EtO) 2 P(O)H and t-BuNH 2 were employed because they have been successfully used in obtaining various a-amino phosphonates and their motif could be easily detected by NMR. 21-23 Thus, this paper describes the synthesis of a-amino phosphonates 5-8 and synthetic approach to them is shortly depicted in Scheme 1.Our synthesis began from protopo...

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The reaction of diethyl phosphonate with Schiff bases derived from aldehydes and ketones in the presence of cadmium iodide is strongly accelerated by microwave irradiation, and the corresponding α-aminophosphonates are formed in high yields.Schiff bases are known to react with diethyl phosphonate to give α-aminophosphonates which constitute an important class of biologically active compounds [1][2][3]. These reactions continuously attract attention from the viewpoints of both stereoselective synthesis of α-aminophosphonates [4,5] and optimization of the reaction conditions [6,7]. The use of microwave irradiation (MW) to accelerate various organic reactions has been well documented [8]. This technique has also found application in the chemistry of organophosphorus compounds. Microwave-assisted Arbuzov reaction [9], arylation of diethyl phosphonate in the presence of metal-complex catalysts [10], Wittig reaction [11], and synthesis of α-aminophosphonates in the three-component system amine-aldehyde-diethyl phosphonate [12,13] have been reported. However, the latter reaction has been performed only with aromatic aldehyde imines.We previously developed a procedure for the synthesis of α-aminophosphonates by reaction of Schiff bases with diethyl phosphonate using CdI 2 as catalyst [6]. The reactions were carried out by heating the reactants to 45°C over a period of 4-10 h, depending on the Schiff base structure. With the goal of optimizing the conditions for the synthesis of both aliphatic and aromatic α-aminophosphonates, in the present work we examined reactions of various aldimines and ketimines with diethyl phosphonate in the presence of CdI 2 under microwave irradiation.We found that a combination of CdI 2 catalysis and microwave irradiation leads to very strong acceleration of the process (the reaction time shortens from 3-10 h to a few minutes or sometimes seconds) and considerable increase in the product yields (see table). The reactions of Schiff bases Ia-Im with diethyl phosphonate were carried out without a solvent in the presence of 5 mol % of CdI 2 under microwave irradiation. The progress of the reactions was monitored by 31 P NMR and IR spectroscopy and thin-layer chromatography. According to the 31 P NMR data, the conversion of both aliphatic and aromatic aldehyde and ketone imines was almost complete, and the corresponding α-aminophosphonates IIa-IIm were isolated in 86-95% yield. It should be noted, that the yield of the final product depended only slightly on the substrate structure. The results are summarized in table. In all cases, the yields of α-aminophosphonates in the microwave-assisted reaction were greater than in the thermal reaction.Less reactive ketimines also readily react with diethyl phosphonate in the presence of CdI 2 under microwave irradation, but the reaction time was longer (up to 10 min). For example, the reactions with N-tertbutylbutylideneamine (Ia) and N-cyclohexylbutylideneamine (Ib) with diethyl phosphonate were complete in 45 s, while ketimines If, Ig, Ij, and Im with I, I...