Potassium carbonate supported efficient synthesis of new diethyl arylphosphoramidates

Abstract

of new diethyl arylphosphoramidatesKeywords: IntroductionPhosphoramidates have gained considerable interest in the last few decades as they have various applications in organic synthesis such as catalytic conversions like aldol and allylation reactions [1]. In addition to catalytic applications, N-arylphosphoramidates have been used as precursors for the synthesis of various heterocycles such as azetidines, aziridines, quinazolinediones and imines [2][3]. Beside this, they are also used to synthesize phosphate esters in nucleotides chemistry [4]. In analytical chemistry, phosphoramidates improve ionization efficiency and suppress matrix-related ion effects in MALDITOF mass spectrometry [5]. In medicinal chemistry, it is reported that phosphoramidates can be used as prodrug moieties to improve therapeutic potential of the parent drug [6]. Phosphoramidates have also served as surrogates for amide bond in the synthesis of peptide based protease inhibitors [7]. They represents some key structure in a number of biologically active natural products like agrocin 84 [8], phosmidosine (II) [9] and GS-6620 (III) [10]. They also form important pharmacophore of many biologically potent compounds e. g. sofosbuvir (IV) (FDA approved drug) used for the treatment of hepatitis C virus (HCV) [11], evofosfamidum (TH-302) (V) which is in clinical trials for cancer treatment (Fig. 1) [12]. Recently, phosphoramidates have also been used in the field of plant hormone as abscisic acid (ABA) agonists that play role in plant growth regulators [13].Among literature methods, direct phosphorylation of different amines with phosphorus halides is one of the most attractive and synthetically accessible methods [14]. Coming to the reactivity, N-phosphorylation of the NH moiety of few N-heterocycles like indoles, imidazoles, and benzimidazole derivatives was reported with the similar reactivity as we expected in alkylations [15]. These phosphoramidates featuring a P-N bond are used as pesticides in agriculture and prodrugs in therapeutic development, and for other synthetic applications [16]. Furthermore, they have been utilized as ligands for metal-catalyzed organic transformations, as flame retardants, and as labelling groups to improve sensitivity in mass spectroscopy [17]. The phosphorylation of a series of amines was studied under different conditions involving the application of the various methods. Our aim was to find the best set of conditions for the preparation of some of these phosphoramidates. ExperimentalGeneral: All reagents were obtained from Sigma-Aldrich and Alfa Aesar and were used directly without further purification. Melting points were recorded on Guna Digital Melting Point apparatus. IR spectra were recorded on Bruker AlphaEco ATR -FTIR interferometer with single reflection sampling module equipped with ZnSe crystal. Chemistry: Initially 0.127 mG (1 mmol) of 4-Chloro aniline (1a) was added to 0.144 mL (1 mmol) diethyl chlorophosphate (2) along with K 2 CO 3 (5 mol%) into a 50 mL round bottom flask in 8mL of DMSO. Then it i...