Synthesis of new functionalized mono‐ and diphosphonic acids with five‐membered aza‐heterocycles moieties

Abstract

The new functionalized hydroxymethylphosphonic and methylenediphosphonic acids are synthesized via unique reaction of tris(trimethylsilyl)phosphite and Nformyl derivatives of five-membered aza-heterocycles at the presence of effective catalyst-trimethylsilyl triflate. Trimethylsilyl esters 1,2 readily react with excess methanol under mild conditions to form water-soluble functionalized mono-or diphosphonic acids, respectively, 3,4 (Scheme 3).The resulting compounds 1-4 can be used for the synthesis of new types of organophosphorus substances, including both heterocyclic fragments and phosphonic groups. These compounds are promising precursors for multitarget drug discovery, perspective plant growth regulators, as well as effective polydentate ligands for various metal complexes with versatile properties.It should be noted that, unlike diethyl acetal formamides, which react readily with esters of phosphorous acid to form N-substituted aminomethylenediphosphonates, [10] reaction of readily available N-diethoxymethyl derivatives of azaheterocycles [11][12][13] with tris(trimethylsilyl) phosphite proceeds via rupture of C-N bonds and leads to diethoxymethylphosphonates 5 in high yields (Scheme 4). | CONCLUSIONSThus, we have proposed the convenient methods of synthesis of new functionalized mono-and diphosphonic acids with five-membered aza-heterocycles moieties via the unique reaction of tris(trimethylsilyl) phosphite with N-formyl azaheterocycles catalyzed by trimethylsilyl triflate. | EXPERIMENTAL | Bis(trimethylsilyl) 1H-imidazol- 1-yl(trimethylsiloxy)methylphosphonate (1a) and tetra(trimethylsilyl) 1H-imidazol-1-ylmethylenediphoshonate (2a)A solution of symm-dicyclohexylcarbodiimide (14.4 g, 0.07 mol) in CH 2 Cl 2 (20 mL) was added under stirring to a solution of 1H-imidazole (3.4 g, 0.05 mol) and formic acid (2.8 g, 0.06 mol) in CH 2 Cl 2 (50 mL). The mixture was stirred for 6 hours and left for 12 hours, then the precipitate is filtered off, the resulting solution was added to a solution of tris(trimethylsilyl) phosphite (44.8 g, 0.15 mol), and a solution of trimethylsilyl triflate (2.9 g, 0.013 mol) in CH 2 Cl 2 (10 mL) was added to this mixture. The mixture was heated in a boiling water bath to complete the stripping of low-boiling compounds and then distilled to give 1.8 g of phosphonate 1a, yield 9%, bp 102°C (1 mm Hg) and diphosphonate (22.0 g) 2a, yield 83%, bp 126°C (1 mm Hg). 4. | 1H-Imidazol-1-yl(hydroxy) methylphosphonic acid (3a)Yield 96%, mp 144-145°C (decomposition ).Phosphonate 5b was obtained similarly.

Synthesis of Aminobisphosphinates through a Cascade Reaction between Hypophosphorous Acid and Bis(trimethylsilyl)imidates Mediated by ZnI2

“…The access to AMBPs is documented in the literature [26]. Indeed, several approaches present the do phosphonylation of amides and nitriles mediated by various Lewis acids [27][28][29][30], a t component reaction of amines with orthoformate and phosphites [31][32][33][34][35][36][37][38][39][40], an Beckmann transposition of oximes in the presence of phosphites [41,42] (Figure Alternatively, only limited examples were reported for the synthesis aminomethylenebisphosphinates (AMBPi) and their biological activities remain unkn to date [43][44][45]. Here, the strategy usually consists of adding in situ pre-formed BTSP ethyl formimidate hydrochloride or onto substituted amides in the presence of TMS respectively (Figure 2c).…”

Synthesis of new functionalized organophosphorus acids and their derivatives with indan‐1‐carboxylic acid moieties

“…Unusual organophosphorus analogs of important amino acids (for example, phenylalanine, tyrosine, tryptophan), including aromatic, heterocyclic, and bicyclic groups, are of particular interest . Recently, we obtained mono‐ and diphosphorus‐substituted proline derivatives, as well as derivatives of mono‐ and diphosphonic acids, including moieties of five‐membered azaheterocycles[7a] with P‐C‐N systems, using trimethylsilyl esters of trivalent phosphorus acid. In this paper, we propose convenient methods for the synthesis of new functionalized organophosphorus acids and their derivatives with indan‐1‐carboxylic acid moieties based on trimethylsilyl esters of trivalent phosphorus acids and specially prepared synthon—trimethylsilyl ester of 1 H ‐indene‐3‐carboxylic acid 1 .…”

Synthesis of new organophosphorus‐substituted fulvenes with indenyl moieties

“…The original synthesis of substituted fulvenes is associated with the radical cyclization of substituted o ‐phenylenediynes in the presence of tributyltin hydride [7]. Preliminary brief data on the synthesis of organophosphorus benzofulvenes were published by us earlier (cf [8a]…”

“…Recently we developed the convenient methods for preparing several organophosphorus compounds with various functional groups and heterocyclic moieties via using of trimethylsilyl esters of organophosphorus acids. [8b]…”