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

Abstract

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.

Relationship between Structure and Antibacterial Activity of α-Aminophosphonate Derivatives Obtained via Lipase-Catalyzed Kabachnik−Fields Reaction

“…The Kabachnik–Fields reaction is the most efficient method for the formation of carbon−phosphorus bonds using an aldehyde, amine, and H -phosphite. A number of other synthetic approaches have also been reported for the preparation of α-aminophosphonates [ 7 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. These methods are generally conducted in the presence of various organic and inorganic bases [ 56 , 57 , ...…”

“…α-Aminophosphonates appear to be a very important class of organic compounds because of their potential biological activities [ 1 , 2 , 3 , 4 ]. The distinctive character of bioactive organophosphorus compounds has established their wide applicability in agricultural and medicinal chemistry [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. α-Aminophosphonates ( Figure 1 ) play a crucial role as a platform to design new drugs [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

Hydroxy- and Amino-Phosphonates and -Bisphosphonates: Synthetic Methods and Their Biological Applications

“…A number of synthetic methods for the synthesis of aminophosphonates have been developed during the past two decades ( Amira et al, 2021 ). Of these methods, the Kabachnik–Fields ( Kaboudin and Moradi, 2005 ) ( Bhagat and Chakraborti, 2007 ) synthesis of 1-aminophosphonates, catalyzed by a base or an acid, is the most convenient method ( Varga and Keglevich 2021 ) ( Sravya et al, 2021 ) ( Supplementary Scheme S2 in SI).…”

Novel α-Aminophosphonates and α-Aminophosphonic Acids: Synthesis, Molecular Docking and Evaluation of Antifungal Activity against Scedosporium Species

“…On the other hand, changing the 1,2,4-triazole for 6fluoro-2,4-pyrimidine and with the addition of a methyl group in the linker, voriconazole is found to have an activity level 5 times greater than its predecessor (IC 50 = 0.002 µM C. albicans) [18,19]; despite these structural modifications, it is still necessary to search for alternative drugs that have a better therapeutic effect and fewer side effects, especially against the Scedosporium genus, since it has shown great resistance to azole antifungals. Thus, there is an important need to develop pharmacological alternatives for the treatment of infections caused by these and other type of fungi [20], so a promising route is the development of novel α-aminophosphonates and α-aminophosphonic monohydrolyzed acids, since these are structural analogues of α-amino acids and there have been previous reports regarding their broad biological activity, such as antiviral [21], anticancer [22], antibacterial [23] and antifungal functions [24]. The α-aminophosphonates could be obtained by the Kabachnik-Fields reaction, which is a one-pot multicomponent reaction between an amine, an aldehyde and a phosphite; there are many reports of conventional synthetic methods and non-conventional ones, such as microwave irradiation (MW) [25], with some of them involving the use of diverse catalysts [26], but there are virtually no reports regarding the synthesis of these compounds assisted by a vortex mixer with no catalysts needed, which constitutes the proposal of the present work.…”