Organophosphorus Chemistry 2018 Printed Edition of the Special Issue Published in Molecules www.mdpi.com/journal/molecules György Keglevich Edited by Organophosphorus Chemistry 2018 Organophosphorus Chemistry 2018 Special Issue Editor Gy ̈ orgy Keglevich MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin Special Issue Editor Gy ̈ orgy Keglevich Department of Organic Chemistry and Technology, Budapest University of Technology and Economics Hungary Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Molecules (ISSN 1420-3049) (available at: https://www.mdpi.com/si/molecules/ Organophosphorus Chemistry). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year , Article Number , Page Range. 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Contents About the Special Issue Editor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Preface to “Organophosphorus Chemistry 2018” . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Gy ̈ orgy Keglevich Editorial to the Organophosphorus Chemistry Special Issue of Molecules (2012–2014) Reprinted from: Molecules 2014 , 19 , 15408-15410, doi:10.3390/molecules191015408 . . . . . . . . 1 Gy ̈ orgy Keglevich and Erika B ́ alint The Kabachnik–Fields Reaction: Mechanism and Synthetic Use Reprinted from: Molecules 2012 , 17 , 12821-12835, doi:10.3390/molecules171112821 . . . . . . . . 3 Artur Mucha Synthesis and Modifications of Phosphinic Dipeptide Analogues Reprinted from: Molecules 2012 , 17 , 13530-13568, doi:10.3390/molecules171113530 . . . . . . . . 17 Anne-Marie Caminade, R ́ egis Laurent, Maria Zablocka and Jean-Pierre Majoral Organophosphorus Chemistry for the Synthesis of Dendrimers Reprinted from: Molecules 2012 , 17 , 13605-13621, doi:10.3390/molecules171113605 . . . . . . . . 51 Elise Bernoud, Romain Veillard, Carole Alayrac and Annie-Claude Gaumont Stoichiometric and Catalytic Synthesis of Alkynylphosphines Reprinted from: Molecules 2012 , 17 , 14573-14587, doi:10.3390/molecules171214573 . . . . . . . . 67 Justyna Siemieniec, Pawel Kafarski and Pawel Plucinski Hydrophosphonylation of Nanoparticle Schiff Bases as a Mean for Preparation of Aminophosphonate-Functionalized Nanoparticles Reprinted from: Molecules 2013 , 18 , 8473-8484, doi:10.3390/molecules18078473 . . . . . . . . . . 81 Lavinia Lupa, Adina Negrea, Mihaela Ciopec and Petru Negrea Cs + Removal from Aqueous Solutions through Adsorption onto Florisil R © Impregnated with Trihexyl(tetradecyl)phosphonium Chloride Reprinted from: Molecules 2013 , 18 , 12845-12856, doi:10.3390/molecules181012845 . . . . . . . . 93 Subhadeep Roy and Marvin Caruthers Synthesis of DNA/RNA and Their Analogs via Phosphoramidite and H-Phosphonate Chemistries Reprinted from: Molecules 2013 , 18 , 14268-14284, doi:10.3390/molecules181114268 . . . . . . . . 105 Vasily P. Morgalyuk Chemistry of Phosphorylated Formaldehyde Derivatives. Part I Reprinted from: Molecules 2014 , 19 , 12949-13009, doi:10.3390/molecules190912949 . . . . . . . . 121 Jarosław Lewkowski, Zbigniew Malinowski, Agnieszka Matusiak, Marta Morawska, Diana Rogacz and Piotr Rychter The Effect of New Thiophene-Derived Aminophosphonic Derivatives on Growth of Terrestrial Plants: A Seedling Emergence and Growth Test Reprinted from: Molecules 2016 , 21 , 694, doi:10.3390/molecules21060694 . . . . . . . . . . . . . . 175 v Jarosław Lewkowski, Maria Rodriguez Moya, Marta Chmielak, Diana Rogacz, Kamila Lewicka and Piotr Rychter Synthesis, Spectral Characterization of Several Novel Pyrene-Derived Aminophosphonates and Their Ecotoxicological Evaluation Using Heterocypris incongruens and Vibrio fisheri Tests Reprinted from: Molecules 2016 , 21 , 936, doi:10.3390/molecules21070936 . . . . . . . . . . . . . . 189 D ́ avid Ill ́ es Nagy, Alajos Gr ̈ un, S ́ andor Garadnay, Istv ́ an Greiner and Gy ̈ orgy Keglevich Synthesis of Hydroxymethylenebisphosphonic Acid Derivatives in Different Solvents Reprinted from: Molecules 2016 , 21 , 1046, doi:10.3390/molecules21081046 . . . . . . . . . . . . . . 203 Ankita Puri and Raakhi Gupta Effect of Mono- and Poly-CH/P Exchange(s) on the Aromaticity of the Tropylium Ion Reprinted from: Molecules 2016 , 21 , 1099, doi:10.3390/molecules21081099 . . . . . . . . . . . . . . 223 Jos ́ e Luis Viveros-Ceballos, Mario Ord ́ o ̃ nez, Francisco J. Sayago and Carlos Cativiela Stereoselective Synthesis of α -Amino- C -phosphinic Acids and Derivatives Reprinted from: Molecules 2016 , 21 , 1141, doi:10.3390/molecules21091141 . . . . . . . . . . . . . . 237 Mario Ord ́ o ̃ nez, Alicia Arizpe, Fracisco J. Sayago, Ana I. Jim ́ enez and Carlos Cativiela Practical and Efficient Synthesis of α -Aminophosphonic Acids Containing 1,2,3,4-Tetrahydroquinoline or 1,2,3,4-Tetrahydroisoquinoline Heterocycles Reprinted from: Molecules 2016 , 21 , 1140, doi:10.3390/molecules21091140 . . . . . . . . . . . . . . 269 Anthony Fers-Lidou, Olivier Berger and Jean-Luc Montchamp Palladium-Catalyzed Allylation/Benzylation of H -Phosphinate Esters with Alcohols Reprinted from: Molecules 2016 , 21 , 1295, doi:10.3390/molecules21101295 . . . . . . . . . . . . . . 283 Anastasy O. Kolodiazhna and Oleg I. Kolodiazhnyi Synthesis, Properties and Stereochemistry of 2-Halo-1,2 λ 5 -oxaphosphetanes Reprinted from: Molecules 2016 , 21 , 1371, doi:10.3390/molecules21101371 . . . . . . . . . . . . . . 299 Ewa Chmielewska and Paweł Kafarski Synthetic Procedures Leading towards Aminobisphosphonates Reprinted from: Molecules 2016 , 21 , 1474, doi:10.3390/molecules21111474 . . . . . . . . . . . . . . 321 Dorota Krasowska, Jacek Chrzanowski, Piotr Kiełbasi ́ nski and J ́ ozef Drabowicz Chiral Hypervalent, Pentacoordinated Phosphoranes Reprinted from: Molecules 2016 , 21 , 1573, doi:10.3390/molecules21111573 . . . . . . . . . . . . . . 347 Marek Cypryk, Jozef Drabowicz, Bartlomiej Gostynski, Marcin H. Kudzin, Zbigniew H. Kudzin and Pawel Urbaniak 1-(Acylamino)alkylphosphonic Acids—Alkaline Deacylation Reprinted from: Molecules 2018 , 23 , 859, doi:10.3390/molecules23040859 . . . . . . . . . . . . . . 391 Raj K. Bansal, Raakhi Gupta and Manjinder Kour Synergy between Experimental and Theoretical Results of Some Reactions of Annelated 1,3-Azaphospholes Reprinted from: Molecules 2018 , 23 , 1283, doi:10.3390/molecules23061283 . . . . . . . . . . . . . . 409 Zita R ́ adai and Gy ̈ orgy Keglevich Synthesis and Reactions of α -Hydroxyphosphonates Reprinted from: Molecules 2018 , 23 , 1493, doi:10.3390/molecules23061493 . . . . . . . . . . . . . . 423 vi Erika B ́ alint, ́ Ad ́ am Tajti, N ́ ora T ́ oth and Gy ̈ orgy Keglevich Continuous Flow Alcoholysis of Dialkyl H -Phosphonates with Aliphatic Alcohols Reprinted from: Molecules 2018 , 23 , 1618, doi:10.3390/molecules23071618 . . . . . . . . . . . . . . 453 Bond Jakub Adamek, A ȱ ¿£¢ǰ Justyna Ko ́ nczewicz, Krzysztof Walczak and Karol Erfurt 1-( N -Acylamino)alkyltriarylphosphonium Salts with Weakened C α -P + Strength—Synthetic Applications Reprinted from: Molecules 2018 , 23 , 2453, doi:10.3390/molecules23102453 . . . . . . . . . . . . . . 469 T ́ ımea R. K ́ egl, No ́ emi P ́ alink ́ as, L ́ aszl ́ o Koll ́ ar and Tam ́ as K ́ egl Computational Characterization of Bidentate P-Donor Ligands: Direct Comparison to Tolman’s Electronic Parameters Reprinted from: Molecules 2018 , 23 , 3176, doi:10.3390/molecules23123176 . . . . . . . . . . . . . . 487 Mehdi Elsayed Moussa, Stefan Welsch, Luis D ̈ utsch, Martin Piesch, Stephan Reichl, Michael Seidl and Manfred Scheer The Triple-Decker Complex [Cp*Fe( μ , η 5 : η 5 -P 5 )Mo(CO) 3 ] as a Building Block in Coordination Chemistry Reprinted from: Molecules 2019 , 24 , 325, doi:10.3390/molecules24020325 . . . . . . . . . . . . . . 499 K. Michał Pietrusiewicz’, Katarzyna Szwaczko, Barbara Mirosław, Izabela Dybała, Radomir Jasi ́ nski and Oleg M. Demchuk New Rigid Polycyclic Bis(phosphane) for Asymmetric Catalysis Reprinted from: Molecules 2019 , 24 , 571, doi:10.3390/molecules24030571 . . . . . . . . . . . . . . 513 Gerhard H ̈ agele Protolysis and Complex Formation of Organophosphorus Compounds—Characterization by NMR-Controlled Titrations Reprinted from: Molecules 2019 , 24 , 3238, doi:10.3390/molecules24183238 . . . . . . . . . . . . . . 535 Lucie Appy, Crystalle Chardet, Suzanne Peyrottes and B ́ eatrice Roy Synthetic Strategies for Dinucleotides Synthesis Reprinted from: Molecules 2019 , 24 , 4334, doi:10.3390/molecules24234334 . . . . . . . . . . . . . . 561 vii About the Special Issue Editor Gy ̈ orgy Keglevich graduated from the Technical University of Budapest in 1981 as a chemical engineer. He received his “Doctor of Chemical Science” degree in 1994, in the subject of organophosphorus-chemistry. He has been the Head of the Department of Organic Chemistry and Technology since 1999. Within organophosphorus chemistry, his major field embraces P-heterocycles, involving selective syntheses as well as bioactive and industrial aspects. He also deals with environmentally friendly chemistry involving MW chemistry, its theoretical aspects, phase transfer catalysis, the development of new chiral catalysts, and the use of ionic liquids. He is the author or co-author of about 550 papers (the majority of which appeared in international journals) including around 70 review articles and 40 book chapters. He is a member of the Editorial Boards of Molecules , Heteroatom Chemistry and Phosphorus, Sulfur and Silicon, and the Related Elements , and Current Microwave Chemistry . He is the Editor-in-Chief of Current Organic Chemistry and Current Green Chemistry , the co-Editor-in-Chief of Current Catalysis , an Associate Editor of Current Organic Synthesis and Letters in Drug Design and Discovery , and a Regional Editor of Letters in Organic Chemistry ix Preface to “Organophosphorus Chemistry 2018” These days, organophosphorus (OP) chemistry forms an integrant part of synthetic organic chemistry. OP compounds are used as starting materials, intermediates, reagents, catalysts (phase transfer catalysts or P(III)-transition metal complexes) and solvents (ionic liquids (IL)) in research laboratories and in the industry. There are many frequently applied reactions, such as reductions, the Wittig reaction and its variations, especially the catalytic versions, the Arbuzov reaction, the Pudovik reaction, the Mitsunobu reaction, or the Kabachnik–Fields reaction, that apply P-containing reagents. The simple deoxygenation of phosphine oxides is also a challenging field. Other reactions e.g. homogeneous catalytic transformations or C-C coupling reactions involve P-ligands in the catalysts. There have been major developments in the field of chiral OP compounds. Methods have been elaborated for the resolution of tertiary phosphine oxides and for stereoselective OP transformations. The optically active P(III) species may be used as ligands in transition metal (Pt, Pd, etc.) complex catalysts, making possible enantioselective transformations. The heterocyclic discipline may include P-heterocycles and classical O- and N-heterocycles with P-functions. A special field comprises P-containing or P-functionalized macrocycles and other macromolecules, like dendrimers. An up-to-date approach is to perform syntheses in the OP discipline in an environmentally-friendly manner. This may include the use of microwave or ultrasound. Solvent-free accomplishments are also interesting. At the other end, OP species (e.g., catalysts and ILs) may be tools in organic chemistry. Monitoring the reactions in order to optimize the conditions, or to observe reactive species, is a challenging field. Theoretical calculation within OP chemistry is a developing field; these days, however, stereostructures and mechanisms may be easily evaluated. A very important segment of OP chemistry, the driving force for development, is the pool of biologically active OP compounds (e.g., bisphosphonic derivatives and aminophosphonic species) that are searched for and used as drugs or plant protecting agents. The natural (e.g., peptide and amino acid) analogue P-compounds should also be mentioned. Many new phosphine oxides, phosphinates, phosphonates and phosphoric esters that may achieve different kinds of application have been described. The OP Special Issue of Molecules will welcome submissions that fit in any way in the above outline. Gy ̈ orgy Keglevich Special Issue Editor xi molecules Editorial Editorial to the Organophosphorus Chemistry Special Issue of Molecules (2012–2014) György Keglevich Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; gkeglevich@mail.bme.hu; Tel.: + 36-1-463-1111 (ext. 5883); Fax: + 36-1-463-3648 Received: 19 September 2014; Accepted: 22 September 2014; Published: 26 September 2014 The review entitled “Organophosphorus Chemistry for the Synthesis of Dendrimers” gives an overview of the methods of synthesis of phosphorus-containing dendrimers, with emphasis on the various roles played by the chemistry of phosphorus [ 1 ]. It is demonstrated that the presence of phosphorus atom(s) at each branching point of the dendrimeric structure is particularly important and highly valuable. The review “Stoichiometric and Catalytic Synthesis of Alkynylphosphines summarizes the possibilities for the preparation of alkynylphosphines that, or their borane complexes, are available either through C–P bond forming reactions, or through modification of the phosphorus or the alkynyl function of various alkynyl phosphorus derivatives [ 2 ]. The latter strategy involving phosphoryl reduction is the method of choice for preparing primary and secondary alkynylphosphines, while the former strategy is employed for the synthesis of tertiary alkynylphosphines, or their borane complexes. Recently e ffi cient catalytic procedures, involving copper complexes and either an electrophilic or a nucleophilic phosphorus reagent have emerged. New developments of the Kabachnik–Fields (K-F) reaction were surveyed in the review “The Kabachnik-Fields Reaction: Mechanism and Synthetic Use” [ 3 ]. The monitoring of a few K–F reactions by in situ Fourier transform IR spectroscopy has indicated the involvement of the imine intermediate that was also justified by theoretical calculations. The K–F reaction was extended to > P(O)H species, comprising cyclic phosphites, acyclic and cyclic H -phosphinates, as well as secondary phosphine oxides. The synthesis under solvent-free microwave conditions is a good method of choice, as sophisticated and environmentally unfriendly catalysts suggested by literature methods are completely unnecessary under microwave conditions. The double K–F reaction made available bis(phosphonomethyl)amines. The paper “Hydrophosphonylation of Nanoparticle Schi ff Bases as a Mean for Preparation of Aminophosphonate-Functionalized Nanoparticles” describes results on magnetic nanoparticles with a modified surface that are attractive alternatives to deliver therapeutic agents [ 4 ]. The surface of the iron oxide nanoparticles was modified with aminophosphonic acids by applying the classical hydrophosphonylation protocol. Recent achievements in the field of phosphinic dipeptide derivatives bearing appropriate side-chain substituents are summarized in the review entitled “Synthesis and Modifications of Phosphinic Dipeptide Analogues” [ 5 ]. Improved methods for the formation of the phosphinic peptide backbone, including stereoselective and multicomponent reactions, are presented. Parallel modifications leading to the structurally diversified substituents are also described, and selected examples of the biomedical applications of the title compounds are given. In the paper “Chemistry of Phosphorylated Formaldehyde Derivatives. Part I.” a few structurally related compounds, such as thioacetals, aminonitriles, aminomethylphosphinoyl compounds, are discussed [ 6 ]. The halogen aminals and acetals of phosphorylated formaldehyde, and a phosphorylated gem-diol of formaldehyde were discussed separately. Molecules 2014 , 19 , 15408-15410; doi:10.3390 / molecules191015408 www.mdpi.com / journal / molecules 1 Molecules 2014 , 19 , 15408-15410 The chemical synthesis of DNA and RNA is usually carried out using nucleoside phosphoramidites or H -phosphonates as synthons. The review “Synthesis of DNA / RNA and their Analogs via Phosphoramidite and H -Phosphonate Chemistries” focuses on the phosphorus chemistry behind these synthons, and how it has been developed [ 7 ]. Additionally, the synthesis and properties of certain DNA and RNA analogues that are modified at the phosphorus atom were also discussed. These analogues include boranephosphonates, metallophosphonates, and alkylboranephosphines. The research “Cesium Ion Removal from Aqueous Solutions through Adsorption onto Florisil ® Impregnated with Trihexyl(tetradecyl)phosphonium Chloride” describes the adsorption performance of Florisil ® impregnated with trihexyl(tetradecyl)phosphonium chloride in the process of cesium ion removal from aqueous solutions [ 8 ]. The adsorption process has been investigated as a function of pH, solid:liquid ratio, adsorbate concentration, contact time, and temperature. References 1. Caminade, A.-M.; Laurent, R.; Zablocka, M.; Majoral, J.-P. Organophosphorus Chemistry for the Synthesis of Dendrimers. Molecules 2012 , 17 , 13605–13621. [CrossRef] 2. Bernoud, E.; Veillard, R.; Alayrac, C.; Gaumont, A.-C. Stoichiometric and Catalytic Synthesis of Alkynylphosphines. Molecules 2012 , 17 , 14573–14587. [CrossRef] 3. Keglevich, G.; B á lint, E. The Kabachnik–Fields Reaction: Mechanism and Synthetic Use. Molecules 2012 , 17 , 12821–12835. [CrossRef] [PubMed] 4. Siemieniec, J.; Kafarski, P.; Plucinski, P. Hydrophosphonylation of Nanoparticle Schi ff Bases as a Mean for Preparation of Aminophosphonate-Functionalized Nanoparticles. Molecules 2013 , 18 , 8473–8484. [CrossRef] [PubMed] 5. Mucha, A. Synthesis and Modifications of Phosphinic Dipeptide Analogues. Molecules 2012 , 17 , 13530–13568. [CrossRef] [PubMed] 6. Morgalyuk, V.P. Chemistry of Phosphorylated Formaldehyde Derivatives. Part I. Molecules 2014 , 19 , 12949–13009. [CrossRef] [PubMed] 7. Roy, S.; Caruthers, M. Synthesis of DNA / RNA and Their Analogs via Phosphoramidite and H -Phosphonate Chemistries. Molecules 2013 , 18 , 14268–14284. [CrossRef] [PubMed] 8. Lupa, L.; Negrea, A.; Ciopec, M.; Negrea, P. Cs + Removal from Aqueous Solutions through Adsorption onto Florisil ® Impregnated with Trihexyl(tetradecyl)phosphonium Chloride. Molecules 2013 , 18 , 12845–12856. [CrossRef] [PubMed] © 2014 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http: // creativecommons.org / licenses / by / 3.0 / ). 2 molecules Review The Kabachnik–Fields Reaction: Mechanism and Synthetic Use György Keglevich 1, * and Erika Bálint 2 1 Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary 2 Research Group of the Hungarian Academy of Sciences, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary * Author to whom correspondence should be addressed; gkeglevich@mail.bme.hu; Tel.: + 36-1-463-1111 (ext. 5883); Fax: + 36-1-463-3648. Received: 18 October 2012; Accepted: 26 October 2012; Published: 1 November 2012 Abstract: The Kabachnik–Fields (phospha-Mannich) reaction involving the condensation of primary or secondary amines, oxo compounds (aldehydes and ketones) and > P(O)H species, especially dialkyl phosphites, represents a good choice for the synthesis of α -aminophosphonates that are of significant importance due to their biological activity. In general, these three-component reactions may take place via an imine or an α -hydroxy-phosphonate intermediate. The monitoring of a few Kabachnik–Fields reactions by in situ Fourier transform IR spectroscopy has indicated the involvement of the imine intermediate that was also justified by theoretical calculations. The Kabachnik–Fields reaction was extended to > P(O)H species, comprising cyclic phosphites, acyclic and cyclic H -phosphinates, as well as secondary phosphine oxides. On the other hand, heterocyclic amines were also used to prepare new α -amino phosphonic, phosphinic and phosphine oxide derivatives. In most cases, the synthesis under solvent-free microwave (MW) conditions is the method of choice. It was proved that, in the cases studied by us, there was no need for the use of any catalyst. Moreover, it can be said that sophisticated and environmentally unfriendly catalysts suggested are completely unnecessary under MW conditions. Finally, the double Kabachnik–Fields reaction has made available bis(phosphonomethyl)amines, bis(phosphinoxidomethyl)amines and related species. The bis(phosphinoxidomethyl)amines serve as precursors for bisphosphines that furnish ring platinum complexes on reaction with dichlorodibenzonitriloplatinum. Keywords: Kabachnik–Fields reaction; α -aminophosphonates; reaction pathway; environmentally friendly; microwave; solventless 1. Introduction The basic method for the preparation of α -aminophosphonates, valuable synthetic equivalents and biologically active substrates, involves the condensation of a primary or secondary amine, a carbonyl compound (aldehyde or ketone) and dialkyl phosphite (Scheme 1) [1,2]. 1+ 2 & 2 3 + 52 52 2 3 & 52 52 1 − + 2 Scheme 1. General scheme for the Kabachnik–Fields reaction. α -Aminophosphonic acids, considered as phosphorus analogues of α -amino acids, have attracted much attention in drug research due to their low mammalian toxicity. They are important targets Molecules 2012 , 17 , 12821-12835; doi:10.3390 / molecules171112821 www.mdpi.com / journal / molecules 3 Molecules 2012 , 17 , 12821-12835 in the development of antibiotics, antiviral species, antihypertensives, and antitumour agents based on their e ff ect as inhibitors of GABA-receptors, enzyme inhibitors and anti-metabolites [ 3 – 9 ]. Diaryl α -amino-phosphonate derivatives are selective and highly potent inhibitors of serine proteases, and thus can mediate the patho-physical processes of cancer growth, metastasis, osteoarthritis or heart failure [ 10 ]. Dialkylglycine decarboxylase [ 9 ] and leucine aminopeptidase [ 11 ] are also inhibited by α -amino-phosphonates. Cyanoacrylate [ 12 ] and amide derivatives [ 13 ] of α -aminophosphonates are active antiviral compounds and inactivators of the tobacco mosaic virus. Certain α -aminophosphonates were proved to be suitable for the design of continuous drug release devices due to their ability to increase the membrane permeability of a hydrophilic probe molecule [14]. 2. Possible Pathways for the Kabachnik–Fields Reaction Cherkasov et al . studied the mechanism of the Kabachnik–Fields reaction in detail. One possibility is that an imine (a Schi ff base) is formed from the carbonyl compound and the (primary) amine, and then the dialkyl phosphite is added on the C = N unit of the intermediate. The other route assumes the formation of an α -hydroxyphosphonate by the addition of the dialkylphosphite to the carbonyl group of the oxo component, then the hydroxyphosphonate undergoes substitution by the amine to furnish the α -aminophosphonate. On the basis of kinetic studies, it was concluded that the mechanism is dependent on the nature of the reactants. For example, the condensation of aniline, benzaldehyde and a dialkyl phosphite was assumed to follow the “imine” mechanism. Interestingly it was found that before the condensation of the aniline and the benzaldehyde, an H-bond is formed between the P = O function of the phosphite and the H N unit of the amine (Scheme 2) [15,16]. 52 3 2 + + 1 + 3K δ 3K&+2 − + 2 52 3 2 + 3K1+ δ− 3K1 &+3K 52 3 2 + 52 3 &+3K 2 1+3K Scheme 2. The “imine” mechanism proposed for a Kabachnik–Fields reaction [15,16]. In another case, Cherkasov et al suggested that the reaction of the more nucleophilic cyclohexyl-amine, benzaldehyde and a dialkyl phosphite takes place via the “hydroxyphosphonate” route. Here again an interaction was substantiated to precede the addition of the dialkylphosphite on the C = O unit of the oxo-compound. According to this, an H-bond is formed between the P(O) H moiety of the phosphite and the nitrogen atom of the amine (Scheme 3) [15,17]. 52 3+ 2 + 1 + 52 3+ 2 1 + + + 3K&+2 52 3 &+ 3K 2+ 2 + 1 + − + 2 52 3 &+ 3K 1+ 2 + δ δ− Scheme 3. The “ α -hydroxyphosphonate” mechanism proposed for a Kabachnik–Fields reaction [ 15 , 17 ]. Later, however, Zefirov and Matveeva proved that the condensation of cyclohexylamine, benzaldehyde and dialkyl phosphite follows the “imine route”, and concluded that there is no real experimental evidence for the hydroxyphosphonate route [ 18 ]. It is also worth mentioning that the reaction of cyclohexylamine, benzaldehyde and dibutylphosphine oxide, that may be regarded as an extended Kabachnik–Fields condensation, was shown to proceed according to the “imine” mechanism [ 15 , 19 ]. It seems probable that the actual mechanism is dependent on the components of the reaction, although the “imine” route seems to be more general than the route involving an 4 Molecules 2012 , 17 , 12821-12835 “ α -hydroxy-phosphonate” intermediate [ 3 ]. R. Gancarz and I. Gancarz substantiated that a reversible formation of the α -hydroxyphosphonate may also occur, and if it is rearranged to the corresponding phosphate, this becomes a “dead-end” route [ 20 ]. It can be said that in the Kabachnik–Fields reaction, a soft nucleophile (the dialkyl phosphite) and a hard nucleophile (the amine) compete for the electrophilic carbonyl compound. The softer the carbonyl compound is, the faster it reacts with the softer P-nucleophile and the slower it reacts with the harder amine nucleophile [21]. We wished to investigate the phospha-Mannich condensation of n -propylamine, benzaldehyde and diethyl phosphite (Scheme 4) by following the reaction utilizing in situ Fourier transform (FT) Infra Red (IR) spectroscopy [22]. 3U1+ 3K& 2 + (W2 3 2 + − + 2 (W2 3 1+3U 2 3K Scheme 4. The Kabachnik–Fields reaction studied by us. The possible reaction paths are shown in Scheme 5. The question was whether the imine 3 or the α -hydroxyphosphonate 4 is the intermediate during the formation of the corresponding α -aminophosphonate 2 3K + 2 3U1+ (W2 3 2 + 3U1+ 3K 2+ (W2 3 (W2 3 2 + Route A Route B 2 3K &+ 13U Scheme 5. Possible routes for the Kabachnik–Fields reaction studied by us. The reaction carried out at 80 ◦ C in acetonitrile was monitored by registering a 3D IR diagram. On the basis of the characteristic ν C = N stretching vibration at 1,648 cm –1 , the imine 3 could be observed as a transient species. It was possible to obtain a relative concentration—time diagram for the components (Figure 1) by deconvolution of the 3D IR diagram. It can be seen that the imine intermediate 3 reaches its maximum concentration after a 10 min reaction time [22]. 5 Molecules 2012 , 17 , 12821-12835 Figure 1. Concentration profile for the Kabachnik–Fields reaction studied at 80 ◦ C in acetonitrile. It was shown above that there was also controversy over the mechanism of the Kabachnik–Fields condensation of cyclohexylamine, benzaldehyde and dialkyl phosphites (Scheme 6) [ 15 , 17 , 18 ]. We sought to clarify the situation by in situ FT IR spectroscopy [23]. + 1 + 3K& + 2 52 3 &+ 3K 1+ + 2 − + 2 52 3 + 2 5 0H D (W E Scheme 6. Another Kabachnik–Fields reaction investigated by us. From among the two possible intermediates 6 and 7 , again the imine 6a could be detected on the basis of the ν C = N = 1,644 cm –1 absorption as the transient species for α -aminophosphonate 5a (Scheme 7). The intermediacy of imine 6 can be seen in Figure 2. + 1 + 1 + 3K&+ 3K& + 2 + 1 + 5 0H D (W E 52 3 + 2 52 3 + 2 5RXWH$ 5RXWH% 3K 2+ 52 3 2 Scheme 7. Possible pathways for the second model investigated. 6 Molecules 2012 , 17 , 12821-12835 Relative concentration Time (h) (MeO) 2 P(O)H PhCH=NC 6 H 11 (MeO) 2 P(O)CH(Ph)NHC 6 H 11 Figure 2. Concentration profile for the Kabachnik–Fields reaction studied at 80 ◦ C in acetonitrile. Relative energies for the possible intermediates 6 and 7 and for α -aminophosphonate 5 were calculated by the B3LYP / 6-31G** method and then refined by the the B3LYP / 6-311G** ++ method provided that dimethyl phosphite is the reactant. It can be seen from Table 1 that the formation of the imine 6 goes with significantly lower energy gain than that of the α -hydroxyphosphonate 7 . On the one hand, the imine 6 would like to be stabilized further by reaction with the dimethyl phosphite on way to the α -aminophosphonate 5 . On the other hand, the hydroxyphosphonate 7 is too stable to react further to the aminophosphonate 5 . The conversion of 7 to 5 represents only a slight energy gain of 2.4 kJ / mol. In other words, there is no significant driving force for the substitution [23]. Table 1. Relative energies for the four states calculated. Species Relative energy (kJ / mol) Reactants (benzaldehyde, cyclohexylamine and dimethyl phosphite) 0.0 Imine intermediate 6 –18.6 α -Hydroxyphosphonate intermediate 7 –40.5 Product 5 –42.9 3. Microwave-Assisted Solvent- and Catalyst-Free Approach for the Synthesis of α -Amino-phosphonates and Related Derivatives Although a lot of catalytic variations to carry out three-component Kabachnik–Fields condensations have been described, we found that the most straightforward synthesis is when the reactants are irradiated with microwave (MW) in the absence of any catalyst or solvent. The solventless and MW-assisted approach was useful in the synthesis of a few α -aminomethylphosphonates [ 24 ]. We used aniline or benzylamine as the amine, formaldehyde, benzaldehyde, acetophenone and cyclohexanone as the oxo-component and dialkyl phosphites and diphenylphosphine oxide as the > P(O)H reactant. The α -aminophosphonates and α -aminophosphine oxide products are represented by structure 8 in general Scheme 8 [ 25 ]. The detailed results are listed in Table 2. The comparative results of the catalytic versions were also included. A detailed account on the conditions of the catalytic reactions is provided in Table 3.Table InTable aTable partTable ofTable theTable casesTable suchTable asTable inTable theTable exampleTable coveredTable byTable reference[ 26 ], the catalytic versions could already be carried out at room temperature. 7