Potassium carbonate supported efficient synthesis of new diethyl arylphosphoramidates P. V. Ramana1, B. S. Krishna1, N. B. Reddy1,2, G. Sravaya1,2, G. V. Zyryanov2,3, C. S. Reddy1 1 Department of Chemistry, Sri Venkateswara University, Tirupati, 517502, India Tel: + 91-9849694958; Fax: + 918772289555 E-mail: csrsvu@gmail.com 2 Department of Organic and Biomolecular Chemistry, Institute of Chemical Engineering, Ural Federal University, 19 Mira St., Ekaterinburg, 620002, Russia 3 Postovsky Institute of Organic Synthesis UB RAS, 22 Kovalevskaya St. / 20 Akademicheskaya St., Ekaterinburg, 620990, Russia of new diethyl arylphosphoramidates Keywords: Introduction Phosphoramidates have gained considerable interest in the last few deca- des as they have various applications in organic synthesis such as catalytic con- versions like aldol and allylation reac- tions [1]. In addition to catalytic applica- tions, 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 ef- ficiency 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]. Phospho- ramidates have also served as surrogates for amide bond in the synthesis of peptide based protease inhibitors [7]. They repre- sents 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 im- portant pharmacophore of many biologi- cally 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 hor- mone 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, imida- zoles, 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 trans- formations, as flame retardants, and as labelling groups to improve sensitivity in mass spectroscopy [17]. The phospho- rylation 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 phos- phoramidates. Experimental General: All reagents were obtained from Sigma-Aldrich and Alfa Aesar and were used directly without further purifi- cation. Melting points were recorded on Guna Digital Melting Point apparatus. IR spectra were recorded on Bruker Alpha – Eco ATR – FTIR interferometer with single reflection sampling module equipped with ZnSe crystal. 1H, 13C and 31P NMR spectra were recorded on Bruker AMX 500 MHz NMR spectrometers ope- rating at 400 MHz for 1H, 100 MHz for 13C and 160 MHz for 31P NMR in DMSO and were referenced to TMS (1H and 13C) and 85 % H3PO4 ( 31P) and their chemical shifts were reported in δ scale. Mass spectra were recorded on a Jeol SX 102 DA/600 mass spectrometer and elemental analy- Fig. 1. Some representative bioactive phosphoramidates sis was performed on a Thermo Finnigan Instrument. Melting points were deter- mined in open capillaries using EZ-Melt automated melting point apparatus. All solvents used for spectroscopic and other physical studies were reagent grade and were further purified by methods report- ed in the literature. 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 K2CO3 (5 mol%) into a 50 mL round bottom flask in 8mL of DMSO. Then it is equipped with a reflux condenser and the contents were heated to 80  °C and reaction was continued at the same temperature and the reaction progress was monitored with TLC (3:7 ratio of ethylacetate and hexane mixture). After completion of the reac- tion the crude contents of diethyl (4-chlo- rophenyl) phosphoramidate (3a) formed were cooled to room temperature and was cooled to room temperature conditions. Then the filtrate was concentrated by re- moving the solvent by rota-evaporation and then it was purified by column chro- matography (1:9 ratio of ethylacetate and hexane mixture) and the pure product 3a was collected. Similarly various amines amines (1a-n) as listed above were used to syn- thesize corresponding diethyl arylphos- phoramidates (3a-n) with good reaction yields by the catalytic action of K2CO3 (5 mol %) in DMSO at 80 °C (Fig. 2). Diethyl (4-chlorophenyl)phospho- ramidate (3a): Yield: 92 %; Brown solid; IR (ZnSe): 3312 (NH  Aromatic), 1172 (P=O), 935 (P-O-Caliphatic) cm -1; 1H NMR (500 MHz, DMSO-d6): δ 1.17–1.33 (6H, m, 2CH3), 3.95 (1H, s, NH), 4.26–4.34 (4H, m, 2CH2), 7.06–7.72 (4H, m, ArH) ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.48, 63.32, 119.26, 127.08, 129.54, 142.22 ppm; 31P NMR (200 MHz, DMSO-d6): δ 2.856 ppm; LC–MS m/z (%): 263 (100) [M+]; Anal. Calcd. for C10H15ClNO3P (%): C, 45.55; H, 5.73; N, 5.31. Found: C, 45.51, H, 5.69; N, 5.28. Diethyl (4-fluorophenyl)phospho- ramidate (3b): Yield: 89 %; Brown solid; IR (ZnSe): 3325 (NH  Aromatic), 1225 (P=O), 942 (P-O-Caliphatic) cm -1; 1H NMR (500 MHz, DMSO-d6): δ 1.20–1.28 (6H, m, 2CH3), 3.87 (1H, s, NH), 4.22–4.26 (4H, m, 2CH2), 6.65–7.06 (4H, m, ArH) ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.42, 62.96, 118.52, 125.85, 132.34, 148.44 ppm; 31P NMR (200 MHz, DMSO-d6): δ 2.824 ppm; LC–MS m/z (%): 247 (100) [M+]; Anal. Calcd. for C10H15ClNO3P (%): C, 48.59; H, 6.12; N, 5.67. Found: C, 48.51; H, 6.06; N, 5.63. Diethyl (4-methoxyphenyl)phospho- ramidate (3c): Yield: 90 %; Brown solid; IR (ZnSe): 3321 (NH  Aromatic), 1212 (P=O), 938 (P-O-Caliphatic) cm -1; 1H NMR (500 MHz, DMSO-d6): δ 1.18–1.29 (6H, m, 2CH3), 3.78–3.84 (3H, m, -O- CH3), 3.89 (1H, s, NH), 4.01–4.12 (4H, m, 2CH2), 6.59–6.94 (4H, m, ArH) ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.38, 55.82, 62.96, 117.33, 121.48, 132.94, 152.31 ppm; 31P NMR (200 MHz, DMSO- d6): δ 2.836 ppm; LC–MS m/z (%): 259 (100) [M+]; Anal. Calcd. for C11H18NO4P (%): C, 50.96; H, 7.00; N, 5.40. Found: C, 50.92; H, 6.95; N, 5.33. Diethyl (5-nitropyridin-2-yl)phos- phoramidate (3d): Yield: 90 %; Brown solid; IR (ZnSe): 3332 (NH  Aromatic), 1194 (P=O), 945 (P-O-Caliphatic) cm -1; 1H NMR (500 MHz, DMSO-d6): δ 1.24–1.31 (6H, m, 2CH3), 3.98 (1H, s, NH), 4.35– 4.46 (4H, m, 2CH2), 7.06–8.72 (4H, m, ArH) ppm; 13C NMR (125 MHz, DMSO- d6): δ 16.36, 62.21, 110.96, 132.08, 136.22, 144.78, 169.14 ppm; 31P NMR (200 MHz, DMSO-d6): δ 2.842 ppm; LC–MS m/z (%): 275 (100) [M+]; Anal. Calcd. for C9H14N3O5P (%): C, 39.28; H, 5.13; N, 15.27. Found: C, 39.24; H, 5.09; N, 15.21. Diethyl (3-fluoro-5-nitrophenyl) phosphoramidate (3e): Yield: 92 %; Brown solid; IR (ZnSe): 3348 (NH  Aro- matic), 1209 (P=O), 944 (P-O-Caliphatic) cm-1; 1H NMR (500 MHz, DMSO-d6): Fig. 2. Synthesis of diethyl arylphosphoramidates δ 1.19–1.32 (6H, m, 2CH3), 4.02 (1H, s, NH), 4.42–4.48 (4H, m, 2CH2), 7.02–7.42 (3H, m, ArH) ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.08, 62.04, 102.05, 104.54, 111.22, 142.08, 150.65, 165.84 ppm; 31P NMR (200 MHz, DMSO-d6): δ 2.816 ppm; LC–MS m/z (%): 292 (100) [M+]; Anal. Calcd. for C10H14FN2O5P (%): C, 41.10; H, 4.83; N, 9.59. Found: C, 41.03; H, 4.80; N, 9.55. Tetraethyl ((phenylazanediyl) b i s ( m e t hy l e n e ) ) d i p h o sp h o r ami d at e (3f ): Yield: 84 %; Brown solid; IR (ZnSe): 3345 (NH  Aromatic), 1246 (P=O), 922 (P-O-Caliphatic) cm -1; 1H NMR (500 MHz, DMSO-d6): δ 1.21–1.32 (12H, m, 4CH3), 1.98 (1H, s, NH), 4.46–4.54 (8H, m, 4CH2), 4.76–4.84 (4H, m, 2CH2), 6.86–7.32 (5H, m, ArH) ppm; 13C NMR (125  MHz, DMSO-d6): δ 16.08, 58.02, 62.22, 115.22, 122.05, 129.44, 150.66 ppm; 31P NMR (200  MHz, DMSO-d6): δ 2.824 ppm; LC–MS m/z (%): 423 (100) [M+]; Anal. Cal- cd. for C16H31N3O6P2 (%): C, 45.39; H, 7.38; N, 9.92. Found: C, 45.35; H, 7.32; N, 9.85. Diethyl thiazol-2-ylphosphoram- idate (3g): Yield: 87 %; Brown solid; IR (ZnSe): 3356 (NH  Aromatic), 1206 (P=O), 938 (P-O-Caliphatic) cm -1; 1H NMR (500 MHz, DMSO-d6): δ 1.28–1.32 (6H, m, 2CH3), 3.95 (1H, s, NH), 4.46–4.54 (4H, m, 2CH2), 6.76–7.62 (2H, m, ArH) ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.36, 62.92, 115.21, 135.48, 169.82 ppm; 31P NMR (200 MHz, DMSO-d6): δ 2.821 ppm; LC–MS m/z (%): 236 (100) [M+]; Anal. Calcd. for C7H13N2O3PS (%): C, 35.59; H, 5.55; N, 11.86. Found: C, 35.53; H, 5.52; N, 11.81. Diethyl (5-ethyl-1,3,4-thiadiazol-2-yl) phosphoramidate (3h): Yield: 86 %; Brown solid; IR (ZnSe): 3315 (NH  Aromatic), 1242 (P=O), 944 (P-O-Caliphatic) cm -1; 1H NMR (500 MHz, DMSO-d6): δ  1.27–1.32 (6H, m, 2CH3), 1.34–1.37 (3H, m, CH3), 2.57–2.62 (2H, m, CH2), 4.05 (1H, s, NH), 4.46–4.54 (4H, m, 2CH2) ppm; 13C NMR (125 MHz, DMSO-d6): δ 11.56, 16.52, 22.36, 62.96, 167.86, 174.14 ppm; 31P NMR (200 MHz, DMSO-d6): δ 2.842 ppm; LC–MS m/z (%): 265 (100) [M+]; Anal. Calcd. for C8H16N3O3PS (%): C, 36.22; H, 6.08; N, 15.84. Found: C, 36.17; H, 6.05; N, 15.75. Diethyl benzo[d][1,3]diox- ol-5-ylphosphoramidate (3i): Yield: 82 %; Brown solid; IR (ZnSe): 3352 (NH  Aro- matic), 1222 (P=O), 953 (P-O-Caliphatic) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 1.27–1.33 (6H, m, 2CH3), 4.01 (1H, s, NH), 4.48–4.54 (4H, m, 2CH2), 6.06–6.09 (2H, m, OCH2O), 6.12–6.65 (3H, m, ArH) ppm; 13C NMR (125 MHz, DMSO- d6): δ 16.08, 62.22, 100.52, 101.33, 109.26, 113.02, 132.88, 139.04, 149.12 ppm; 31P NMR (200 MHz, DMSO-d6): δ 2.836 ppm; LC–MS m/z (%): 273 (100) [M+]; Anal. Calcd. for C11H16NO5P (%): C, 48.36; H, 5.90; N, 5.13. Found: C, 48.33; H, 5.85; N, 5.05. Diethyl (2-(1H-indol-3-yl)ethyl) phosphoramidate (3j): Yield: 84 %; Brown solid; IR (ZnSe): 3344 (NH  Aro- matic), 1251 (P=O), 958 (P-O-Caliphatic) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 1.28–1.34 (6H, m, 2CH3), 2.04 (1H, s, NH), 2.78–2.84 (2H, m, CH2), 2.92–2.94 (2H, m, CH2), 4.47–4.52 (4H, m, 2CH2), 7.16–7.42 (5H, m, ArH), 10.04 (1H, s, Indole NH) ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.05, 31.02, 43.95, 62.32, 111.23, 114.26, 118.98, 119.84, 122.08, 124.54 ppm; 31P NMR (200 MHz, DMSO- d6): δ 10.252 ppm; LC–MS m/z (%): 296 (100) [M+]; Anal. Calcd. for C14H21N2O3P (%): C, 56.75; H, 7.14; N, 9.45. Found: C, 56.71; H, 7.10; N, 9.39. Diethyl (5-nitrothiazol-2-yl)phos- phoramidate (3k): Yield: 80 %; Brown solid; IR (ZnSe): 3352 (NH  Aromatic), 1216 (P=O), 946 (P-O-Caliphatic) cm -1; 1H NMR (500 MHz, DMSO-d6): δ 1.27–1.31 (6H, m, 2CH3), 4.01 (1H, s, NH), 4.50– 4.54 (4H, m, 2CH2), 8.62 (1H, s, ArH) ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.54, 62.32, 136.26, 147.38, 165.94 ppm; 31P NMR (200 MHz, DMSO-d6): δ 2.812 ppm; LC–MS m/z (%): 281 (100) [M+]; Anal. Calcd. for C7H12N3O5PS (%): C, 29.90; H, 4.30; N, 14.94. Found: C, 29.85; H, 4.26; N, 14.90. Diethyl (2-(piperidin-2-yl)ethyl) phosphoramidate (3l): Yield: 82 %; Brown solid; IR (ZnSe): 3362 (NH  Aro- matic), 1214 (P=O), 953 (P-O-Caliphatic) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 1.28–1.35 (6H, m, 2CH3), 1.56–1.64 (8H, m, 4CH2), 2.04 (1H, s, NH), 2.66 (1H, s, CH), 2.76–2.82 (4H, m, 2CH2), 4.45–4.52 (4H, m, 2CH2), ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.28, 23.32, 26.85, 32.82, 35.06, 39.32, 47.02, 59.02, 62.22 ppm; 31P NMR (200 MHz, DMSO-d6): δ 10.232 ppm; LC–MS m/z (%): 264 (100) [M+]; Anal. Calcd. for C11H25N2O3P (%): C, 49.99; H, 9.53; N, 10.60. Found: C, 49.95; H, 9.50; N, 10.54. Diethyl (furan-2-ylmethyl)phospho- ramidate (3m): Yield: 86 %; Brown solid; IR (ZnSe): 3348 (NH  Aromatic), 1209 (P=O), 968 (P-O-Caliphatic) cm -1; 1H NMR (500 MHz, DMSO-d6): δ 1.22–1.32 (6H, m, 2CH3), 1.96 (1H, s, NH), 3.72–3.76 (2H, m, CH2), 4.49–4.54 (4H, m, 2CH2), 6.46–7.62 (3H, m, ArH) ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.22, 35.01, 62.12, 110.26, 110.48, 142.54, 148.82 ppm; 31P NMR (200 MHz, DMSO-d6): δ 7.824 ppm; LC–MS m/z (%): 233 (100) [M+]; Anal. Calcd. for C9H16NO4P (%): C, 46.35; H, 6.92; N, 6.01. Found: C, 46.30; H, 6.88; N, 5.94. Diethyl 1H-benzo[d]imida- zol-1-ylphosphonate (3n): Yield: 84 %; Brown solid; IR (ZnSe): 3356 (NH  Aro- matic), 1198 (P=O), 959 (P-O-Caliphatic) cm-1; 1H NMR (500 MHz, DMSO-d6): δ 1.26–1.34 (6H, m, 2CH3), 4.50–4.53 (4H, m, 2CH2), 7.26–7.62 (4H, m, ArH), 8.18 (1H, s, N=CH-N) ppm; 13C NMR (125 MHz, DMSO-d6): δ 16.22, 60.12, 115.26, 124.08, 137.84, 139.05, 142.25 ppm; 31P NMR (200 MHz, DMSO-d6): δ –6.724 ppm; LC–MS m/z (%): 254 (100) [M+]; Anal. Calcd. for C11H15N2O3P (%): C, 51.97; H, 5.95; N, 11.02. Found: C, 51.93; H, 5.91; N, 10.96. Results and Discussion At the onset of our investigation for the synthesis of phosphoramidate de- rivatives, 4-Chloro aniline and diethyl chlorophosphate were taken as model substrates to optimize the experimental conditions. Initially, 4-chloro aniline and diethyl chlorophosphate were heated at 80 °C in DMSO without any catalyst, but the reaction was unable to produce the product even after the prolonged heating for 48 h (Table 1, entry 1). Hence, we have traced the activity of various catalysts for the synthesis of Diethyl(4-chlorophenyl) phosphoramidate (3a). The catalytic ef- fect of such inorganic and organic bases (Table 1, entries 2–11) afforded the pro- ducts with low yield, where K2CO3 only afforded maximum product yields in 8  h of reaction time (Table 1, entries 12–14). In the catalyst optimization studies with 2, 5 and 10 mol% of K2CO3, we obtained the yields were 68, 94 and 94 respectively (Ta- ble 1, Entries 12–14). Therefore, 5 mol % of K2CO3 was sufficient for completion of the reaction and excess amount of catalyst did not increase the yields and the reus- ability of the catalyst has not also been ob- served with the mark of satisfaction. Then several solvents, such as DMF, 1,4-dioxane, acetone, MeCN, THF, CH3NO2, CH3CH2OH, and dimethylsul- foxide were screened in the presence of 5 mol% of K2CO3 at 80  °C (Table 2, entries 1–8), and the results showed that dimethyl- sulfoxide (DMSO) was the best choice. Conclusions We have been successful in accom- plishing a new synthetic protocol for the construction of phosphoramidates scaf- fold under sustainable condition applying K2CO3 catalysis. Developed synthetic pro- tocol offers various advantages like op- erational simplicity, low catalyst loading, an extensive substrate scope, and a high product yield. The use of DMSO as the re- action medium and application of K2CO3 catalyst make this protocol truly a practi- cal one for synthetic chemistry. Acknowledgements Acknowledgements: We thank Prof. C. Devendranath Reddy, Department of Chemistry, S. V. University, Tirupati for his helpful discussions and Science and Engineering Research Board (SERB), New Delhi – 110 070 India for providing financial assistance through a research project grant F. No.: SB/S1/OC-96/2013, Dt: 05–11–2014. Table 1 Influence of various catalysts on the synthesis of compound 4a at 80 °C Entry Catalyst Catalyst (mol %) Time (h) Yield (%) 1 None – 48 NR 2 Cs2CO3 5 10 65 3 Na2CO3 5 12 45 4 NaOH 5 24 NR 5 t-BuOH 5 10 42 6 NaHCO3 5 10 38 7 K3PO4·3H2O 5 24 NR 8 AcOK 5 24 NR 9 DBU 5 14 Trace 10 Et3N 5 10 24 11 Pyridine 5 10 15 12 K2CO3 2 8 68 13 K2CO3 5 8 94, 89, 82 14 K2CO3 10 8 94 Table 2 Effect of various solvents on the synthesis of compound 4a Entry Solvent Time (h) Yield (%) 1 DMF 8 74 2 1,4-dioxane 8 72 3 Acetone 8 68 4 MeCN 8 75 5 THF 8 82 6 CH3NO2 8 42 7 CH3CH2OH 8 84 8 DMSO 8 94 References 1. Egron D, Imbach JL, Gosselin G, Aubertin AM, Perigaud C. S-Acyl-2-thioethyl Phosphoramidate Diester Derivatives as Mononucleotide Prodrugs. J Med Chem. 2003;46(21):4564–71. DOI:10.1021/jm0308444. 2. Denmark SE, Chung WJ. Lewis Base Activation of Lewis Acids: Catalytic Enan- tioselective Glycolate Aldol Reactions. Angew Chem Int Ed. 2008;47(10):1890–2. DOI:10.1002/anie.200705499. 3. 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DOI:0.1021/acs.biochem.5b01144. Cite this article as (как цитировать эту статью) Ramana PV, Krishna BS, Reddy NB, Sravaya G, Zyryanov GV, Reddy C S. Potassium carbonate supported efficient synthesis of new diethyl arylphosphoramidates. Chimica Techno Acta. 2017;4(2):148–156. DOI:10.15826/chimtech.2017.4.2.030.