Methods for the synthesis of α -heterocyclic/heteroaryl-α -aminophosphonic acids and their esters

This review describes a comprehensive account of methods which are commonly applied for the synthesis of α -heterocyclic/heteroaryl α -aminophosphonic acids and their esters. In the following order, protocols based on the methodologies listed below are discussed: (a) Pudovik reaction; (b) Kabachnik-Fields reaction and (c) Miscellaneous Methods.


Introduction
α-Aminophosphonic acids are considered mimics of the corresponding α-aminocarboxylic acid. 1 The phosphonic moiety has long been established as a bioisostere of a carboxylic unit.3][4][5] They have been found in areas ranging from medicine to agriculture, for example, as antibiotics, 6 enzyme inhibitors, 7 anticancer agents 8 and herbicides. 9,10These biological properties mostly are associated with the tetrahedral structure of the phosphonyl group acting as a "transition-state" analogue. 11Because of their ability to mimic transition states of hydrolysis, phosphonic acid derivatives having heterocycles at the α-positions have been shown to be inhibitors of various enzymes, including HIV-protease and human collagenase. 12t present, the literature concerning the synthesis and application of α-aminophosphonates is very extensive, comprising more than six thousand publications.Hence, several approaches 13 have been developed for the synthesis of α-aminophosphonates.Two main pathways are: (i) the Pudovik reaction, where dialkyl phosphites are added to imines, and (ii) the Kabachnik-Fields three component reaction, in which a carbonyl, an amine and a di-or tri-alkyl phosphite react in a single-pot.In some reports, these reactions were carried out as straightforward one-pot procedures without any catalyst, 14 but in most cases they were performed using catalysts. 15On the other hand, α-aminophosphonic acids and their esters bearing a heterocyclic moiety at the α-position are becoming the subject of growing interest.To our knowledge, there are several methods for the synthesis of α-heterocyclic/heteroaryl α-aminophosphonates (Figure 1).In connection with our work on the preparation of α-aminophosphonates containing heterocyclic systems, [16][17][18][19] we report in this review article all the available synthetic methods of α-heterocyclic/heteroaryl α-aminophosphonates which were published until 2013.

Five-membered heterocycles with one heteroatom
The Schiff bases 1 were subjected to react in situ with diethyl phosphite in toluene at 110 °C to give the corresponding α-aminophosphonate esters 2. When diphenyl phosphite was used in the reaction with imines 1, the addition reaction took place even at room temperature, giving the diphenyl esters in high yields (Scheme 1). 20

Scheme 3
Reaction of the Schiff bases 8 with dialkyl phosphites in toluene at 85 o C provided the corresponding α-aminophosphonates 9 (Scheme 4). 24 85 o C

Scheme 4
The diethyl phosphonate esters 11 were prepared by heating equimolar mixtures of diethyl phosphite and the corresponding Schiff base 10 in the absence of solvent at temperatures between 90 and 100 ºC (Scheme 5). 25

Scheme 8
Similarly, addition of diethyl phosphite to the azomethine bonds of the bis-Schiff base 19 was carried out, affording 1,3-bis[N-[(diethoxyphosphonyl)-(2-furyl)methyl]amino]benzene (20).In this case NMR studies revealed that the reaction product is a mixture of the two possible diastereomeric forms: R,S (meso) and the enantiomeric pair R,R and S,S (Scheme 9).

Scheme 9
Also, four bis(aminophosphonates) 25, 26, 27 and 28 were synthesized through addition of diethyl phosphite to the azomethine bonds of the furan-substituted bis(imines) 21-24.The addition of dialkyl (diaryl) phosphites to bis(imines) should lead to the formation of two diastereomeric forms, meso and racemic diastereomers.Thus, this synthesis in most cases occurs with high stereoselectivity, yielding as major product only one of the diastereomers, as previously obtained in similar reactions (Scheme 10). 30,31

Scheme 10
Poly(oxyethylene)aminophosphonates 31 were synthesized through addition of poly (oxyethylene H-phosphonates) 29 to the azomethine bond of N-furfurylidene toluidine (30), according to Scheme 11.The polymer analogous reaction was carried out in the presence of catalytic CdI 2 , as well as without catalyst.In the presence of CdI 2 the addition of P-H groups to the azomethine 30 proceeded with higher reaction rate compared to the non-catalyzed reaction and the poly (α-aminophosphonates) 31 were obtained in good yields in 3 hours.In the absence of catalyst the reaction time was longer, up to 15 hours (Scheme 11).

Scheme 12
Reaction of the Schiff bases 34 with diethyl hydrogen phosphite via Pudovik reaction in refluxing toluene in the absence of catalyst afforded the corresponding α-aminophosphonates 35 (Scheme 13).

Scheme 15
The diethyl 1,3-benzodioxylphosphonate esters 43 were prepared by heating equimolar mixtures of diethyl phosphite and the corresponding Schiff base 42 in the absence of solvent at temperatures between 90 and 100 °C (Scheme 16). 25  Scheme 17

N
1-(N-Benzyl)-2-formyl-5-benzyloxy-pyridone 47 reacted with primary amines to obtain the corresponding imines 48.The imines then were treated with a mixture of trimethyl phosphite and bromotrimethylsilane, which caused in situ formation of tris(trimethylsilyl) phosphite, which instantly reacted with the imines, giving silylated phosphonate intermediates.Treatment of the intermediates with methanol caused removal of the silylated groups and the formation of the final α-(pyridinyl)-α-aminophosphonic acids 49 (Scheme 18).

Scheme 19
Some piperidine-incorporated α-aminophosphonates 54 were prepared in excellent yields by reacting imines 53 with triethyl phosphite in the presence of dilute HCl under ultrasound irradiation (Scheme 20). 40

Scheme 25
Similarly, the addition of diethyl phosphite to compounds 66 was carried out in dry benzene containing few drops of triethylamine as catalyst to yield the corresponding bis-(α-aminophosphonate) derivatives 67 (Scheme 26). 47lso, addition of diethyl phosphite to azomethine bonds of interesting compounds 68 and 69 on fusion at 80-100 °C in the presence of a catalytic amount of triethylamine yielded one diastereomeric form of tetraethyl 5,

Scheme 38
][84][85] Three-component Mannich type reactions starting from aldehydes or ketones, amines and phosphites have proved to be a facile method for the preparation of various α-aminoalkylphosphonate compounds.A rapid method for the synthesis of N-phosphoramino-αaminophosphonate 92 involved reacting veratraldehyde with diethyl phosphoramidate and a cyclic trivalent chlorophosphite at 50-60 °C neat, without solvent or catalyst, for an appropriate time (Scheme 40).

Scheme 51
The target α-aminophosphonates 116 were synthesized via the Mannich-type reactions of aldehyde 115, aromatic amines, and dialkyl phosphites or triphenyl phosphite in the presence of Mg(ClO 4 ) 2 in moderate to good yields.It was found that Mg(ClO 4 ) 2 can reduce the reaction time and improve the yields of products greatly (Scheme 52). 99© ARKAT-USA, Inc

Scheme 52
The reaction of 10-ethyl-10H-phenothiazine-3-carbaldehyde 117, anilines, and diethyl phosphite in PEG-400 was complete in 24 hour at room temperature; the corresponding αaminophosphonates 118 was obtained in low yield (30%).However, the yield was dramatically increased by increasing the temperature to 100 °C.Under optimized conditions, the reaction proceeded well at 100 °C and the desired α-aminophosphonate 118 (Ar=Ph) was obtained in 91% yield.PEG-400 was found to be more effective in the synthesis of 118 (Ar=Ph) in terms of reaction time (6 h) and yields (91%) (Scheme 53).

Conclusions
During the last few years, the α-aminophosphonic acids have attracted considerable attention in the scientific community and a great variety of methodologies have been reported for the synthesis of these compounds.The importance of having new relevant structures has allowed the development of new strategies and synthetic procedures.The authors of this review have collected the most relevant procedures reported up to the end 2013 on the synthesis of αheterocyclic/heteroaryl α-aminophosphonic acids and their esters that will be a fundamental key in the design of new bioactive agents with improved pharmacological properties.The review is built up according to the used methods and starting with the smallest rings of each method.

Tarik
El-Sayed Ali was born in Cairo, Egypt, in 1975.He is presently assistant professor of Organic Chemistry, Department of Chemistry, Faculty of Education, Ain Shams University, Cairo, Egypt.He graduated with B.Sc. (Physics and Chemistry) from Ain Shams University in 1997.He received his M.Sc.and Ph.D. degrees in 2001 and 2005, respectively, in Heterocyclic Chemistry from Ain Shams University.Awarded a post doctoral scientific grant for supporting young researchers (2007) from the Ministry of High Education and Scientific Research (Egypt) in organophosphorus laboratory, Institute of Polymers, Bulgarian Academy of Science, Sofia, Bulgaria.His CV was included in Who's Who in the World in 2011, 2012, 2013 and 2015.He won the award for the best research article in the field of Heterocyclic Chemistry at the Egyptian universities and research centers in 2011.He has published more than 40 scientific papers including 10 review articles, all in international journals.His research interests are in synthesis and chemical reactivity of phosphorus compounds containing bioactive heterocyclic systems.Somaia M. Abdel-Karim was born in 1985 in Cairo, Egypt.In 2006 she graduated from Ain Shams University, Faculty of Education, Department of Chemistry.Also, she received her M.Sc.and Ph.D. degrees in 2011 and 2014, respectively, in Organophosphorus Chemistry.She has published about 10 scientific papers, all in international journals.Her research interests are in synthesis and chemical reactivity of phosphorus compounds containing bioactive heterocyclic systems.

Table 1 .
69ntinuedRefluxing thiophene-2-carbaldehyde with a mixture of urea and diethyl phosphite in dry toluene afforded the ureidophosphonate 73 as a major product (Scheme 29).69

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The optimized reaction conditions involved refluxing of the phosphonyliminium salt 147 and some nucleophilic aromatic compounds in THF gave the highest yields of novel αheteroaryl-α-aminophosphonates 151 (Scheme 66).