Synthesis of α-Aminophosphonates and Related Derivatives; The Last Decade of the Kabachnik–Fields Reaction

The Kabachnik–Fields reaction, comprising the condensation of an amine, oxo compound and a P-reagent (generally a >P(O)H species or trialkyl phosphite), still attracts interest due to the challenging synthetic procedures and the potential biological activity of the resulting α-aminophosphonic derivatives. Following the success of the first part (Molecules 2012, 17, 12821), here we summarize the synthetic developments in this field accumulated in the last decade. The procedures compiled include catalytic accomplishments as well as catalyst-free and/or solvent-free “greener” protocols. The products embrace α-aminophosphonates, α-aminophosphinates, and α-aminophosphine oxides along with different bis derivatives from the double phospha-Mannich approach. The newer developments of the aza-Pudovik reactions are also included.


Introduction
The Kabachnik-Fields reaction involves the condensation of a primary or secondary amine, an oxo compound such as an aldehyde or ketone, and a >P(O)H-containing reagent, which is in most cases a dialkyl phosphite, but may also be an alkyl-H-phosphinate or a secondary phosphine oxide, to result in the formation of α-aminophosphonates, α-aminophosphinates, and α-aminophosphine oxides, respectively [1][2][3][4][5]. The classical version of the "phospha-Mannich" reaction was discovered independently by Kabachnik and Fields more than sixty years ago [6,7].
The α-aminophosphonic and α-aminophosphinic derivatives incorporating an N-C-P moiety are still a focus due to their real or potential biological activity. The acid derivatives of the species under discussion may be regarded as the analogues of their natural counterparts, carboxylic acids. As such, as a consequence of their different properties (tetrahedral P vs. planar C, different acidity, and steric bulk) they are recognized by receptors and enzymes as false substrates/inhibitors [8][9][10][11][12]. The bioactivity realized in this way may be manifested in applications as agrochemicals and medicines.
The mechanism of the phospha-Mannich reaction depends on the nature of the substrates applied. It has been said that the condensation may proceed via an imine (Schiff base) or α-hydroxyphosphonate intermediate (Scheme 1/route "A" and "B" respectively) [13][14][15].
The number of publications describing different variations of the Kabachnik-Fields reaction exceeds 450 papers. The usual phospha-Mannich protocol includes the condensation of equimolar quantities of the three components in organic solvents and the use of various catalysts, comprising in most cases Lewis and Brönsted acids. A wide range of catalysts have been described, such as metal perchlorates; Amberlysts; succinic-, sulfonic-, and oxalic-acids; zinc, iron, and niobium salt; lanthanide triflates; boron trifluoride etherate; titanium dioxide; etc. [16]. However, it has been found that catalyst-free methods may also be appropriate, especially under solvent-free and/or microwave-assisted condi-tions [17][18][19][20][21][22][23]. The latter protocols represent green chemical approaches that are the focus of this article.

Ar
A series of α-aminophosphonate derivatives (21) incorporating an uracil moiety was synthesized using Mg(ClO 4 ) 2 as the catalyst and acetonitrile as the solvent at 80 • C (Scheme 12) [35]. The products showed potential herbicidal activity. A series of α-aminophosphonate derivatives (21) incorporating an uracil moiety was synthesized using Mg(ClO4)2 as the catalyst and acetonitrile as the solvent at 80 °C (Scheme 12) [35]. The products showed potential herbicidal activity.  Cu/Au and Gd oxide nanocatalysts allowed the efficient condensation of different amines, benzaldehyde derivatives, and dimethyl phosphite under conventional heating or under microwave (MW) irradiation (Schemes 15 and 16) [38,39]. The use of these catalysts gave the corresponding products (22 and 24) in similar yields. Cu/Au and Gd oxide nanocatalysts allowed the efficient condensation of different amines, benzaldehyde derivatives, and dimethyl phosphite under conventional heating or under microwave (MW) irradiation (Schemes 15 and 16) [38,39]. The use of these catalysts gave the corresponding products (22 and 24) in similar yields. Cu/Au and Gd oxide nanocatalysts allowed the efficient condensation of different amines, benzaldehyde derivatives, and dimethyl phosphite under conventional heating or under microwave (MW) irradiation (Schemes 15 and 16) [38,39]. The use of these catalysts gave the corresponding products (22 and 24) in similar yields. Dehydroascorbic acid (DHAA)-capped magnetite nanoparticles were successfully applied in the phospha-Mannich condensation of aromatic amines and aldehydes with dimethyl phosphite (Scheme 17) [40]. A deep eutectic solvent (DES) comprising ZrOCl2 · 8H2O and urea in a 1:5 ratio made possible the efficient condensation of aryl-(heteroaryl)aldehydes, aniline derivatives and dimethyl phosphite at room temperature. The role of the DES was to serve as a reaction medium and as a catalyst (Scheme 18) [41].
Scheme 18. Kabachnik-Fields reaction with a DES as the solvent and the catalyst. Dehydroascorbic acid (DHAA)-capped magnetite nanoparticles were successfully applied in the phospha-Mannich condensation of aromatic amines and aldehydes with dimethyl phosphite (Scheme 17) [40]. Dehydroascorbic acid (DHAA)-capped magnetite nanoparticles were successfully applied in the phospha-Mannich condensation of aromatic amines and aldehydes with dimethyl phosphite (Scheme 17) [40]. A deep eutectic solvent (DES) comprising ZrOCl2 · 8H2O and urea in a 1:5 ratio made possible the efficient condensation of aryl-(heteroaryl)aldehydes, aniline derivatives and dimethyl phosphite at room temperature. The role of the DES was to serve as a reaction medium and as a catalyst (Scheme 18) [41]. A deep eutectic solvent (DES) comprising ZrOCl 2 ·8H 2 O and urea in a 1:5 ratio made possible the efficient condensation of aryl-(heteroaryl)aldehydes, aniline derivatives and dimethyl phosphite at room temperature. The role of the DES was to serve as a reaction medium and as a catalyst (Scheme 18) [41].
In the above discussion, metal-catalyzed reactions are summarized. The application of metal catalysts makes possible efficient condensations, most of which occur at room temperature; however, these methods, especially the ones applying Zn or Ni promoters, cannot be considered environmentally friendly. At the same time, MW-assisted and solventfree approaches may be considered as green techniques. Scheme 17. Dehydroascorbic-acid-catalyzed Kabachnik-Fields reactions.
A deep eutectic solvent (DES) comprising ZrOCl2 · 8H2O and urea in a 1:5 ratio made possible the efficient condensation of aryl-(heteroaryl)aldehydes, aniline derivatives and dimethyl phosphite at room temperature. The role of the DES was to serve as a reaction medium and as a catalyst (Scheme 18) [41].
Scheme 18. Kabachnik-Fields reaction with a DES as the solvent and the catalyst.
In the above discussion, metal-catalyzed reactions are summarized. The application of metal catalysts makes possible efficient condensations, most of which occur at room temperature; however, these methods, especially the ones applying Zn or Ni promoters, cannot be considered environmentally friendly. At the same time, MW-assisted and solvent-free approaches may be considered as green techniques.

Acid-Catalyzed Kabachnik-Fields Reactions
The Kabachnik-Fields condensations outlined in the next section are promoted by acidic catalysts. The reaction of aniline derivatives, substituted benzaldehydes, and dimethyl phosphite was performed using a bifunctional acid-base catalyst (IRMOF-3, where MOF is a metal organic framework: Zn 4 O(H 2 N-TA) 3 prepared from 2-aminoterephthalic acid (H 2 ATA) and Zn(NO 3 ) 2 ·6H 2 O) (Scheme 19) [42]. The other option was to use a sulfated polyborate as the catalyst (Scheme 20) [43]. When applying IRMOF-3 and sulfated polyborate as the catalyst, the corresponding products were formed in similar yields.

Acid-Catalyzed Kabachnik-Fields Reactions
The Kabachnik-Fields condensations outlined in the next section are promoted by acidic catalysts. The reaction of aniline derivatives, substituted benzaldehydes, and dimethyl phosphite was performed using a bifunctional acid-base catalyst (IRMOF-3, where MOF is a metal organic framework: Zn4O(H2N-TA)3 prepared from 2-aminoterephthalic acid (H2ATA) and Zn(NO3)2•6H2O) (Scheme 19) [42]. The other option was to use a sulfated polyborate as the catalyst (Scheme 20) [43]. When applying IRMOF-3 and sulfated polyborate as the catalyst, the corresponding products were formed in similar yields.  An efficient method was developed for the preparation of α-aminophosphonates (26), which involved applying phenylboronic acid as the catalyst under solvent-free conditions at 50 °C (Scheme 21) [44]. Phenylphosphonic acid was found to be an efficient reusable heterogeneous catalyst in the three-component phospha-Mannich reaction of benzylamine, aldehydes/ketones, and dimethyl phosphite (Scheme 22) [45]. Phenylphosphonic acid was found to be an efficient reusable heterogeneous catalyst in the three-component phospha-Mannich reaction of benzylamine, aldehydes/ketones, and dimethyl phosphite (Scheme 22) [45].  The condensation of aminophenols, benzaldehyde derivatives, and dimethyl phosphite was performed in an aqueous medium containing oxalic acid as the catalyst at 90 °C. No yields were achieved (Scheme 23) [46]. The condensation of aminophenols, benzaldehyde derivatives, and dimethyl phosphite was performed in an aqueous medium containing oxalic acid as the catalyst at 90 • C. No yields were achieved (Scheme 23) [46].
The condensation of aminophenols, benzaldehyde derivatives, and dimethyl phosphite was performed in an aqueous medium containing oxalic acid as the catalyst at 90 °C. No yields were achieved (Scheme 23) [46].
The latter approach provided the α-aminophosphonates in almost quantitative yields.
In another, more general example, a highly efficient biodegradable supramolecular polymer-supported catalyst was applied (Scheme 24) [47]. The catalyst represents a green component.

Scheme 23. Oxalic-acid-catalyzed Kabachnik-Fields reactions.
The latter approach provided the α-aminophosphonates in almost quantitative yields. In another, more general example, a highly efficient biodegradable supramolecular polymer-supported catalyst was applied (Scheme 24) [47]. The catalyst represents a green component.  The readily available paratoluenesulfonic acid (PTSA) was found to be a suitable catalyst in a series of phospha-Mannich reactions. The thoroughly investigated model reaction is shown in Scheme 25 [48]. The readily available paratoluenesulfonic acid (PTSA) was found to be a suitable catalyst in a series of phospha-Mannich reactions. The thoroughly investigated model reaction is shown in Scheme 25 [48]. Scheme 24. Application of biodegradable supramolecular polymer-supported catalyst in the Kabachnik-Fields reaction.
The readily available paratoluenesulfonic acid (PTSA) was found to be a suitable catalyst in a series of phospha-Mannich reactions. The thoroughly investigated model reaction is shown in Scheme 25 [48].
PTSA was also used in the condensation of different amines, formaldehyde, and secondary phosphine oxides in toluene at the boiling point (Scheme 26) [49]. The yields of products 29 and 30 were ≥90%. The readily available paratoluenesulfonic acid (PTSA) was found to be a suitable catalyst in a series of phospha-Mannich reactions. The thoroughly investigated model reaction is shown in Scheme 25 [48].
PTSA was also used in the condensation of different amines, formaldehyde, and secondary phosphine oxides in toluene at the boiling point (Scheme 26) [49]. The yields of products 29 and 30 were ≥90%. New α-aminophosphine oxides and α-aminophosphonates (32/33) were made available by the PTSA-catalyzed reaction of amines containing an acetal group (31), paraformaldehyde, and >P(O)H reagents (Schemes 27 and 28) [50,51]. No yields were achieved for the second series of reactions.   Solvent-free realizations may be typically associated with MW irradiation. This was the case with the polystyrene-supported PTSA-catalyzed condensation of 2-aminofluorene (34), a number of aldehydes, and dimethyl phosphite (Scheme 29) [52]. β-Cyclodextrin-supported sulfonic acid was also used as an efficient and reusable heterogeneous catalyst in the preparation of thiazolylaryl α-aminophosphonates (37) (Scheme 30) [53]. Solvent-free realizations may be typically associated with MW irradiation. This was the case with the polystyrene-supported PTSA-catalyzed condensation of 2-aminofluorene (34), a number of aldehydes, and dimethyl phosphite (Scheme 29) [52].

Scheme 31.
Eaton's reagent used as a catalyst in the condensations.
The condensation of the basic model (aniline derivatives, substituted benzaldehydes, and diethyl phosphite) was also performed with water as the medium, using different organic acid catalysts (Scheme 32) [55]. The yields were variable. Potassium hydrogen sulfate also proved to be a powerful catalyst in the above type of reaction (Scheme 33) [56]. The condensation of the basic model (aniline derivatives, substituted benzaldehydes, and diethyl phosphite) was also performed with water as the medium, using different organic acid catalysts (Scheme 32) [55]. The yields were variable.

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2-Cyclopropylpyridimidine-4-carbaldehyde (40) was also used as the starting material in three-component condensations. In one case, phosphomolybdic acid was applied as the catalyst (Scheme 34) [57]; in another, camphor-derived thiourea organocatalysts (42,43) were utilized (Scheme 35) [58]. The yields of products (41) were mostly high. (40)  Zeolite derivatives such as H-β zeolite and MCM-41 were applied as green catalysts in different kinds of three-component condensations under discussion (Schemes 36 and 37) [59,60]. In the second series, quinoline-4-carbaldehyde (44) was the oxo component.  Regarding the acid-catalyzed Kabachnik-Fields reactions, those applying water as the solvent or a biodegradable catalyst, or those that may be performed under solventfree conditions, can be considered "green". PTSA has been used in various Kabachnik-Fields reactions as an efficient catalyst. The application of other acidic catalysts (camphorderived thiourea catalysts, H-β zeolite, MCM-41) gave the corresponding products in variable yields.
The phospha-Mannich reaction of 5-hydroxymethyl-furan-1-carbaldehyde (46) with aniline and diethyl phosphite was catalyzed by elemental iodine, allowing the condensation under mild conditions (Scheme 38) [61]. It is noteworthy that 2-methyltetrahydrofuran was used as a green solvent. The yields of the α-aminophosphonates (47) were variable. It was proven that the reaction proceeds via the imine pathway, which is followed by the nucleophilic attack of the diethyl phosphite to furnish the α-aminophosphonate. The role of iodine is to activate the imine(s) in the nucleophilic addition. Iodine may act as a Lewis acid [61].
α-(Furfurylamino)-alkylphosphonates (49) were synthesized by the Kabachnik-Fields reaction of furfurylamine (48), aromatic aldehydes, and dialkyl phosphites under MW irradiation. Silica-gel-supported iodine was used as the catalyst under solvent-free conditions. The plant growth regulatory activity of the products was investigated (Scheme 39) [62]. Regarding the acid-catalyzed Kabachnik-Fields reactions, those applying water as the solvent or a biodegradable catalyst, or those that may be performed under solventfree conditions, can be considered "green". PTSA has been used in various Kabachnik-Fields reactions as an efficient catalyst. The application of other acidic catalysts (camphorderived thiourea catalysts, H-β zeolite, MCM-41) gave the corresponding products in variable yields.
The phospha-Mannich reaction of 5-hydroxymethyl-furan-1-carbaldehyde (46) with aniline and diethyl phosphite was catalyzed by elemental iodine, allowing the condensation under mild conditions (Scheme 38) [61]. It is noteworthy that 2-methyltetrahydrofuran was used as a green solvent. The yields of the α-aminophosphonates (47)  Regarding the acid-catalyzed Kabachnik-Fields reactions, those applying water as the solvent or a biodegradable catalyst, or those that may be performed under solventfree conditions, can be considered "green". PTSA has been used in various Kabachnik-Fields reactions as an efficient catalyst. The application of other acidic catalysts (camphorderived thiourea catalysts, H-β zeolite, MCM-41) gave the corresponding products in variable yields.
The phospha-Mannich reaction of 5-hydroxymethyl-furan-1-carbaldehyde (46) with aniline and diethyl phosphite was catalyzed by elemental iodine, allowing the condensation under mild conditions (Scheme 38) [61]. It is noteworthy that 2-methyltetrahydrofuran was used as a green solvent. The yields of the α-aminophosphonates (47) were variable. It was proven that the reaction proceeds via the imine pathway, which is followed by the nucleophilic attack of the diethyl phosphite to furnish the α-aminophosphonate. The role of iodine is to activate the imine(s) in the nucleophilic addition. Iodine may act as a Lewis acid [61].
α-(Furfurylamino)-alkylphosphonates (49) were synthesized by the Kabachnik-Fields reaction of furfurylamine (48), aromatic aldehydes, and dialkyl phosphites under MW irradiation. Silica-gel-supported iodine was used as the catalyst under solvent-free conditions. The plant growth regulatory activity of the products was investigated (Scheme 39) [62]. It was proven that the reaction proceeds via the imine pathway, which is followed by the nucleophilic attack of the diethyl phosphite to furnish the α-aminophosphonate. The role of iodine is to activate the imine(s) in the nucleophilic addition. Iodine may act as a Lewis acid [61].

Catalyst-Free Kabachnik-Fields Reactions
Having discussed the catalyst-promoted Kabachnik-Fields condensations, let us focus instead on the catalyst-free variations, which represent an environmentally friendly approach. The application of ionic liquids (50 or 51) as the solvent allowed the condensation of the three-components at room temperature (Scheme 41 (1) and (2)) [64]. Both mono-(4) and bis products (52) were identified. The yields were variable, and fell in the range of 25-96%. There were no data provided on the recycling of the ionic liquids.

Catalyst-Free Kabachnik-Fields Reactions
Having discussed the catalyst-promoted Kabachnik-Fields condensations, let us focus instead on the catalyst-free variations, which represent an environmentally friendly approach. The application of ionic liquids (50 or 51) as the solvent allowed the condensation of the three-components at room temperature (Scheme 41 (1) and (2)) [64]. Both mono-(4) and bis products (52) were identified. The yields were variable, and fell in the range of 25-96%. There were no data provided on the recycling of the ionic liquids.
Catalyst-free accomplishment of the phospha-Mannich condensation applying glycerol as the solvent.
A series of new α-sulfamidophosphonates and cyclosulfamidophosphonates incor porating quinoline or a quinolone moiety was synthesized by the Kabachnik-Fields reac tion in the presence of a suitable ionic liquid under ultrasound irradiation [71].  Glycerol could also be used as the solvent in the catalyst-free condensation of amines, arylaldehydes, and phosphites (Scheme 46) [70].
Catalyst-free accomplishment of the phospha-Mannich condensation applying glycerol as the solvent.
A series of new α-sulfamidophosphonates and cyclosulfamidophosphonates incorporating quinoline or a quinolone moiety was synthesized by the Kabachnik-Fields reaction in the presence of a suitable ionic liquid under ultrasound irradiation [71]. A series of new α-sulfamidophosphonates and cyclosulfamidophosphonates incorporating quinoline or a quinolone moiety was synthesized by the Kabachnik-Fields reaction in the presence of a suitable ionic liquid under ultrasound irradiation [71].
It was rather surprising that carboxylic acid amides could also be utilized as starting materials in the Kabachnik-Fields reaction. However, the amides had to be applied in a 10-fold excess under practically solvolytic and forcing conditions (Scheme 57) [87].
It was rather surprising that carboxylic acid amides could also be utilized as starting materials in the Kabachnik-Fields reaction. However, the amides had to be applied in a 10-fold excess under practically solvolytic and forcing conditions (Scheme 57) [87].

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Optically active α-phenylethylamine used as the amine component in the Kabachnik-Fields reaction; conversion of the product to a ring Pt complex.
It was rather surprising that carboxylic acid amides could also be utilized as starting materials in the Kabachnik-Fields reaction. However, the amides had to be applied in a 10-fold excess under practically solvolytic and forcing conditions (Scheme 57) [87].

Scheme 58. Synthesis and derivatization of bis(phosphine oxides).
α-Hydroxyphosphonates formed reversibly from suitable ketones and dialkyl phosphites [89] may also be converted to α-aminophosphonates by substitution reaction with amines. This reaction is enhanced by an adjacent group effect [90,91].
In the third part of the first section, green methods utilizing MW irradiation were summarized. These solvent-and catalyst-free protocols produce α-aminophosphonates, α-aminophosphinates, and phosphine oxides, along with their bis and tris derivatives in good yields. The advantages of applying MW irradiation include the mild reaction conditions, selectivity, and high yields. To compare the methods described, it goes without saying that MW-assisted accomplishment is the most suitable method to synthesize αaminophosphonates and their derivatives. In the third part of the first section, green methods utilizing MW irradiation were summarized. These solvent-and catalyst-free protocols produce α-aminophosphonates, α-aminophosphinates, and phosphine oxides, along with their bis and tris derivatives in good yields. The advantages of applying MW irradiation include the mild reaction conditions, selectivity, and high yields. To compare the methods described, it goes without saying that MW-assisted accomplishment is the most suitable method to synthesize α-aminophosphonates and their derivatives.

Kabachnik-Fields Reactions Leading to Optically Active α-Aminophosphonates
Optically active α-aminophosphine oxides (98) were synthesized from the ethyl ester of proline (97), benzaldehyde derivatives, and diphenylphosphine oxide in toluene at reflux (Scheme 60) [93]. The chiral center in the proline derivative influenced the enantioselectivity. In the third part of the first section, green methods utilizing MW irradiation were summarized. These solvent-and catalyst-free protocols produce α-aminophosphonates, α-aminophosphinates, and phosphine oxides, along with their bis and tris derivatives in good yields. The advantages of applying MW irradiation include the mild reaction conditions, selectivity, and high yields. To compare the methods described, it goes without saying that MW-assisted accomplishment is the most suitable method to synthesize α-aminophosphonates and their derivatives.

Kabachnik-Fields Reactions Applying Trialkyl Phosphites or Related Derivatives as the P Reagent
In the next section, Kabachnik-Fields condensations applying trialkyl phosphites and related derivatives are discussed. Primary amines, 4-(4′-pyridyl)benzaldehyde (100), and triethyl phosphite were condensed in the presence of PEG-SO3H in toluene at 40-50 °C to give the corresponding aminophosphonates (101) (Scheme 62) [95]. In the above examples, the application of optically active amines as the starting materials allowed a diastereoselectivity of 74-92%.

Kabachnik-Fields Reactions Applying Trialkyl Phosphites or Related Derivatives as the P Reagent
In the next section, Kabachnik-Fields condensations applying trialkyl phosphites and related derivatives are discussed. Primary amines, 4-(4 -pyridyl)benzaldehyde (100), and triethyl phosphite were condensed in the presence of PEG-SO 3 H in toluene at 40-50 • C to give the corresponding aminophosphonates (101) (Scheme 62) [95]. In the above examples, the application of optically active amines as the starting ma terials allowed a diastereoselectivity of 74-92%.

Kabachnik-Fields Reactions Applying Trialkyl Phosphites or Related Derivatives as the P Reagent
In the next section, Kabachnik-Fields condensations applying trialkyl phosphite and related derivatives are discussed. Primary amines, 4-(4′-pyridyl)benzaldehyde (100 and triethyl phosphite were condensed in the presence of PEG-SO3H in toluene at 40-5 °C to give the corresponding aminophosphonates (101) (Scheme 62) [95]. Hafnium(IV) chloride was found to be an efficient catalyst in the condensation o amines/diamines, aldehydes, and trialkyl phosphites using ethanol as the solvent at 60 °C (Scheme 68) [100]. Hafnium(IV) chloride was found to be an efficient catalyst in the condensation of amines/diamines, aldehydes, and trialkyl phosphites using ethanol as the solvent at 60 • C (Scheme 68) [100]. Hafnium(IV) chloride was found to be an efficient catalyst in the condensation of amines/diamines, aldehydes, and trialkyl phosphites using ethanol as the solvent at 60 °C (Scheme 68) [100]. The following example for condensation in water involves the reaction of aniline and benzaldehyde derivatives with triethyl phosphite, utilizing a SO3H-functionalized ionic liquid as the catalyst (Scheme 69) [101]. The following example for condensation in water involves the reaction of aniline and benzaldehyde derivatives with triethyl phosphite, utilizing a SO 3 H-functionalized ionic liquid as the catalyst (Scheme 69) [101].
The three-component reactions were also realized under ultrasonic irradiation at 26 °C in an ethyl lactate-water mixture (Scheme 70) [102]. Under these conditions, the corresponding products were obtained in good yields. Ultrasound activation allowed a solvent-and catalyst-free condensation of aniline and benzaldehyde derivatives with triethyl phosphite (Scheme 71) [103]. The three-component reactions were also realized under ultrasonic irradiation at 26 • C in an ethyl lactate-water mixture (Scheme 70) [102]. Under these conditions, the corresponding products were obtained in good yields.
The three-component reactions were also realized under ultrasonic irradiation at 26 °C in an ethyl lactate-water mixture (Scheme 70) [102]. Under these conditions, the corresponding products were obtained in good yields. Ultrasound activation allowed a solvent-and catalyst-free condensation of aniline and benzaldehyde derivatives with triethyl phosphite (Scheme 71) [103]. Ultrasound activation allowed a solvent-and catalyst-free condensation of aniline and benzaldehyde derivatives with triethyl phosphite (Scheme 71) [ We now consider further solvent-free methods.
[Emim][Br] was found to be an efficient catalyst in the neat condensation of different amines, aldehydes, and phosphites, allowing the use of temperatures as low as 26 °C (Scheme 72) [104]. A solvent-free sonochemical transformation utilized a magnetically recoverable composite catalyst (Scheme 73) [105].
Scheme 73. The use of a magnetically recoverable catalyst in the Kabachnik-Fields reaction. PMA-phosphor molybdic acid.
Boric acid was a suitable catalyst for the condensation of amines, benzaldehyde derivatives, and trimethyl phosphite (Scheme 74) [106].

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Scheme 73. The use of a magnetically recoverable catalyst in the Kabachnik-Fields reaction. PMA-phosphor molybdic acid.
Boric acid was a suitable catalyst for the condensation of amines, benzaldehyde derivatives, and trimethyl phosphite (Scheme 74) [106].
Scheme 74. Boric acid as the catalyst in a solvent-free reaction.
Dicationic ionic liquids were used as recyclable catalysts in the solvent-free synthesis of aminophosphonates starting from primary amines, benzaldehyde derivatives, and trimethyl phosphite (Scheme 75) [107]. Dicationic ionic liquids were used as recyclable catalysts in the solvent-free synthesis of aminophosphonates starting from primary amines, benzaldehyde derivatives, and trimethyl phosphite (Scheme 75) [107].
Scheme 74. Boric acid as the catalyst in a solvent-free reaction.
To compare the methods with each other, a few studies have been performed in solvents, like the protocol using T3P, which gives the products in good yields. On the other hand, a few other methods applying Fe3O4@SiO2-imid PMA and H3BO3 as the catalysts in a solvent-free manner have been to give the corresponding products in good yields. The advantage of using dicationic ionic liquids is that the catalysts are recyclable. These issues are of importance from the point of view of green chemistry. These methods play an important role in allowing mild conditions, reducing the reaction times, and giving the products in high yields. However, if the Kabachnik-Fields reactions utilizing dialkyl phosphites and trialkyl phosphites are compared, the protocol applying dialkyl phosphites (see subchapter 3) is unambiguously the method of choice due to its atomic efficiency. Moreover, trialkyl phosphites have an unpleasant smell.

The aza-Pudovik Reaction
The aza-Pudovik reaction involving the addition of a dialkyl phosphite to an imine is another approach to synthesize α-aminophosphonates. A carbazole-related imine (109) was reacted with dialkyl phosphites and diphenylphosphine oxide in the presence of tetramethylguanidine as the catalyst in toluene to give the corresponding adducts (110) in A few other Kabachnik-Fields reactions followed by intramolecular cyclization have also been described. Ordóñez et al. elaborated the MW-assisted condensation of 2formylbenzoic acid, aromatic amines (including optically active ones), and dimethyl phosphite [109][110][111] or triethyl phosphite [112] to afford the corresponding isoindolin-1-one-phosphonates after a ring closure in the final step.
To compare the methods with each other, a few studies have been performed in solvents, like the protocol using T3P, which gives the products in good yields. On the other hand, a few other methods applying Fe 3 O 4 @SiO 2 -imid PMA and H 3 BO 3 as the catalysts in a solvent-free manner have been to give the corresponding products in good yields. The advantage of using dicationic ionic liquids is that the catalysts are recyclable. These issues are of importance from the point of view of green chemistry. These methods play an important role in allowing mild conditions, reducing the reaction times, and giving the products in high yields. However, if the Kabachnik-Fields reactions utilizing dialkyl phosphites and trialkyl phosphites are compared, the protocol applying dialkyl phosphites (see subchapter 3) is unambiguously the method of choice due to its atomic efficiency. Moreover, trialkyl phosphites have an unpleasant smell.

The aza-Pudovik Reaction
The aza-Pudovik reaction involving the addition of a dialkyl phosphite to an imine is another approach to synthesize α-aminophosphonates. A carbazole-related imine (109) was reacted with dialkyl phosphites and diphenylphosphine oxide in the presence of tetramethylguanidine as the catalyst in toluene to give the corresponding adducts (110) in good yields (Scheme 77) [113]. A cinchona-derived thiourea (117)(118)(119)(120)(121)(122) was applied in the addition of diphenyl phosphite to ketimines (Scheme 79) [115]. The yields of products 114 and 116 varied within the range of 48-88%. In another case, the simple starting materials benzylideneimines were reacted with secondary phosphine oxides, where a guanidium salt (112) served as the catalyst (Scheme 78) [114]. In another case, the simple starting materials benzylideneimines were reacted with secondary phosphine oxides, where a guanidium salt (112) served as the catalyst (Scheme 78) [114].
Theoretical calculations predicted that the aza-Pudovik reaction under discussion takes place in a single concerted step involving transition state (136) formed from the trivalent tautomeric form of dimethyl phosphite and N-benzylideneaniline (Scheme 86) [121]. It was shown that the aza-Pudovik reaction involving the addition of >P(O)H reagents into the unsaturation of imines is a good and atomically efficient route for the preparation of α-aminophosphonic derivatives. As a matter of fact, as was shown in the Introduction, imines are intermediates of the Kabachnik-Fields reactions that may be formed from the oxo component and the amine.

Conclusions
In conclusion, various methods for the synthesis of α-aminophosphonic derivatives utilizing the Kabachnik-Fields reaction are summarized herein. In this review, different approaches utilizing a wide range of catalysts are summarized, encompassing the results of the last decade. We focused on environmentally friendly points of view. The solventfree MW-assisted methods are of special importance. The Kabachnik-Fields reaction is also suitable for the synthesis of bis derivatives. Beside >P(O)H reagents, trialkyl phosphites may also be used as the starting materials of the phospha-Mannich condensation. The aza-Pudovik reaction is a special variation for the preparation of α-aminophosphonic derivatives and related compounds.  In another approach, poly(aminophosphonates) were prepared in a one-pot manner including Kabachnik-Fields condensation and polymerization [123]. Functional polymers with bis(phosphonomethyl)amine moieties were also prepared. In this case, phosphorous acid was the P component [124].
Theoretical calculations predicted that the aza-Pudovik reaction under discussion takes place in a single concerted step involving transition state (136) formed from the trivalent tautomeric form of dimethyl phosphite and N-benzylideneaniline (Scheme 86) [121]. In another approach, poly(aminophosphonates) were prepared in a one-pot manner including Kabachnik-Fields condensation and polymerization [123]. Functional polymers with bis(phosphonomethyl)amine moieties were also prepared. In this case, phosphorous acid was the P component [124].
Theoretical calculations predicted that the aza-Pudovik reaction under discussion takes place in a single concerted step involving transition state (136) formed from the trivalent tautomeric form of dimethyl phosphite and N-benzylideneaniline (Scheme 86) [121]. It was shown that the aza-Pudovik reaction involving the addition of >P(O)H reagents into the unsaturation of imines is a good and atomically efficient route for the preparation of α-aminophosphonic derivatives. As a matter of fact, as was shown in the Introduction, imines are intermediates of the Kabachnik-Fields reactions that may be formed from the oxo component and the amine.

Conclusions
In conclusion, various methods for the synthesis of α-aminophosphonic derivatives utilizing the Kabachnik-Fields reaction are summarized herein. In this review, different approaches utilizing a wide range of catalysts are summarized, encompassing the results of the last decade. We focused on environmentally friendly points of view. The solventfree MW-assisted methods are of special importance. The Kabachnik-Fields reaction is also suitable for the synthesis of bis derivatives. Beside >P(O)H reagents, trialkyl phosphites may also be used as the starting materials of the phospha-Mannich condensation. The aza-Pudovik reaction is a special variation for the preparation of α-aminophosphonic derivatives and related compounds.  It was shown that the aza-Pudovik reaction involving the addition of >P(O)H reagents into the unsaturation of imines is a good and atomically efficient route for the preparation of α-aminophosphonic derivatives. As a matter of fact, as was shown in the Introduction, imines are intermediates of the Kabachnik-Fields reactions that may be formed from the oxo component and the amine.

Conclusions
In conclusion, various methods for the synthesis of α-aminophosphonic derivatives utilizing the Kabachnik-Fields reaction are summarized herein. In this review, different approaches utilizing a wide range of catalysts are summarized, encompassing the results of the last decade. We focused on environmentally friendly points of view. The solvent-free MW-assisted methods are of special importance. The Kabachnik-Fields reaction is also suitable for the synthesis of bis derivatives. Beside >P(O)H reagents, trialkyl phosphites may also be used as the starting materials of the phospha-Mannich condensation. The aza-Pudovik reaction is a special variation for the preparation of α-aminophosphonic derivatives and related compounds.