Synthesis of (1,2,3-triazol-4-yl)methyl Phosphinates and (1,2,3-Triazol-4-yl)methyl Phosphates by Copper-Catalyzed Azide-Alkyne Cycloaddition

An efficient and practical method was developed for the synthesis of new (1,2,3-triazol-4-yl)methyl phosphinates and (1,2,3-triazol-4-yl)methyl phosphates by the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) of organic azides and prop-2-ynyl phosphinate or prop-2-ynyl phosphate. The synthesis of (1-benzyl-1H-1,2,3-triazol-4-yl)methyl diphenylphosphinate was optimized with respect to the reaction parameters, such as the temperature, reaction time, and catalyst loading. The approach was applied to a range of organic azides, which confirmed the wide scope and the substituent tolerance of the process. The method elaborated represents a novel approach for the synthesis of the target compounds.


Results and Discussion
At first, the starting materials of the cycloadditions were prepared. The synthesis of azides was carried out based on the literature data [26,27] (Scheme 5). The benzyl or substituted benzyl bromides were reacted with 1.5 equivalents of sodium azide at room temperature for 24 h in a mixture of acetone/water in a ratio of 4:1, and the corresponding azides (9a-f) were obtained in yields of 80-93% (Scheme 5/I, Method A). The synthesis of octyl-, i-octyland cyclohexyl azides (9g-i) was performed using 1.2 equivalents of sodium azide at 70 • C in dimethylformamide (DMF) (Scheme 5/I, Method B). For the preparation of phenyl azide (11), aniline was reacted with sodium nitrite in HCl/H 2 O solution at 0 • C for 15 min, and the diazonium salt (10) formed was further reacted with sodium azide at ambient temperature (Scheme 5/II). After workup, phenyl azide (11) was obtained in a yield of 65%.
Molecules 2019, 24, 2085 3 of 14 To the best of our knowledge, there is no example for the azide-alkyne cycloaddition of simple azides and prop-2-ynyl phosphinate or diethyl prop-2-ynyl phosphate. The reaction of prop-2-ynyl diphenylphosphinate was reported only with steroidal azides [25]. Hence, we set a sight on building a phosphinate or phosphate side-chain on position 4 of the triazole ring by the click reaction with simple azides.

Results and Discussion
At first, the starting materials of the cycloadditions were prepared. The synthesis of azides was carried out based on the literature data [26,27] (Scheme 5). The benzyl or substituted benzyl bromides were reacted with 1.5 equivalents of sodium azide at room temperature for 24 h in a mixture of acetone/water in a ratio of 4:1, and the corresponding azides (9a-f) were obtained in yields of 80-93% (Scheme 5/I, Method A). The synthesis of octyl-, i-octyl-and cyclohexyl azides (9g-i) was performed using 1.2 equivalents of sodium azide at 70 °C in dimethylformamide (DMF) (Scheme 5/I, Method B). For the preparation of phenyl azide (11), aniline was reacted with sodium nitrite in HCl/H2O solution at 0 °C for 15 min, and the diazonium salt (10) formed was further reacted with sodium azide at ambient temperature (Scheme 5/II). After workup, phenyl azide (11) was obtained in a yield of 65%. The synthesis of the prop-2-ynyl diphenylphosphinate (12a) and the diethyl prop-2-ynyl phosphate (12b) was carried out by the reaction of diphenylphosphinic chloride or diethyl chlorophosphate with propargyl alcohol in the presence of triethylamine in diethyl ether (Scheme 6). The phosphorus-containing alkynes (12a and 12b) were isolated in yields of 88% and 72%, respectively. Scheme 6. Synthesis of prop-2-ynyl phosphinate (12a) and diethyl prop-2-ynyl phosphate (12d).
The synthesis of the prop-2-ynyl diphenylphosphinate (12a) and the diethyl prop-2-ynyl phosphate (12b) was carried out by the reaction of diphenylphosphinic chloride or diethyl chlorophosphate with propargyl alcohol in the presence of triethylamine in diethyl ether (Scheme 6). The phosphorus-containing alkynes (12a and 12b) were isolated in yields of 88% and 72%, respectively. To the best of our knowledge, there is no example for the azide-alkyne cycloaddition of simple azides and prop-2-ynyl phosphinate or diethyl prop-2-ynyl phosphate. The reaction of prop-2-ynyl diphenylphosphinate was reported only with steroidal azides [25]. Hence, we set a sight on building a phosphinate or phosphate side-chain on position 4 of the triazole ring by the click reaction with simple azides.

Results and Discussion
At first, the starting materials of the cycloadditions were prepared. The synthesis of azides was carried out based on the literature data [26,27] (Scheme 5). The benzyl or substituted benzyl bromides were reacted with 1.5 equivalents of sodium azide at room temperature for 24 h in a mixture of acetone/water in a ratio of 4:1, and the corresponding azides (9a-f) were obtained in yields of 80-93% (Scheme 5/I, Method A). The synthesis of octyl-, i-octyl-and cyclohexyl azides (9g-i) was performed using 1.2 equivalents of sodium azide at 70 °C in dimethylformamide (DMF) (Scheme 5/I, Method B). For the preparation of phenyl azide (11), aniline was reacted with sodium nitrite in HCl/H2O solution at 0 °C for 15 min, and the diazonium salt (10) formed was further reacted with sodium azide at ambient temperature (Scheme 5/II). After workup, phenyl azide (11) was obtained in a yield of 65%. The synthesis of the prop-2-ynyl diphenylphosphinate (12a) and the diethyl prop-2-ynyl phosphate (12b) was carried out by the reaction of diphenylphosphinic chloride or diethyl chlorophosphate with propargyl alcohol in the presence of triethylamine in diethyl ether (Scheme 6). The phosphorus-containing alkynes (12a and 12b) were isolated in yields of 88% and 72%, respectively. Scheme 6. Synthesis of prop-2-ynyl phosphinate (12a) and diethyl prop-2-ynyl phosphate (12d).
a Isolated yield.

General
The reactions under conventional heating were carried out in an oil bath. The microwave-assisted experiments were performed in a 300 W CEM Discover focused microwave reactor (CEM Microwave Technology Ltd., Buckingham, UK) equipped with a pressure controller using 5-10 W irradiation under isothermal conditions.
High-performance liquid chromatography-mass spectrometry (HPLC-MS) measurements were performed with an Agilent 1200 liquid chromatography system coupled with a 6130 quadrupole mass spectrometer equipped with an ESI ion source (Agilent Technologies, Palo Alto, CA, USA). Analysis was performed at 40 • C on a Gemini C18 column (150 mm × 4.6 mm, 3 µm; Phenomenex, Torrance, CA, USA) with a mobile phase flow rate of 0.6 mL/min. The composition of eluent A was 0.1% (NH 4 )(HCOO) in water; eluent B was 0.1% (NH 4 )(HCOO) and 8% water in acetonitrile, 0-3 min 5% B, 3-13 min gradient, 13-20 min 100% B. The injection volume was 5 µL. The chromatographic profile was registered at 254 nm. The MSD operating parameters were as follows: positive ionization mode, scan spectra from m/z 120 to 1200, drying gas temperature 300 • C, nitrogen flow rate 10 L/min, nebulizer pressure 60 psi, capillary voltage 4000 V.
High-resolution mass spectrometric measurements were performed using a Sciex 5600+ Q-TOF (time-of-flight) mass spectrometer in positive electrospray mode.
The 31 P, 1 H, 13 C, NMR spectra were taken in CDCl 3 solution on a Bruker AV-300 spectrometer (Bruker AXS GmBH, Karlsruhe, Germany) operating at 121.5, 75.5, and 300 MHz, respectively. Chemical shifts are downfield relative to 85% H 3 PO 4 and TMS (spectra for all compounds synthesized can be found in Supplementary).

General Procedure for the Synthesis of Benzyl Azides (Method A)
To a stirred solution of 10.0 mmol alkyl halides (1.19 mL of benzyl bromide, 1.85 g of 4-methylbenzyl bromide, 1.21 mL of 2-fluorobenzyl bromide, 1.23 mL of 3-fluorobenzyl bromide, 1.25 mL of 4-fluorobenzyl bromide, or 1.55 mL of 4-(trifluoromethyl)benzyl bromide) in 100 mL of acetone/H 2 O 4:1 (v/v) was added 15.0 mmol (0.98 g) of sodium azide. The reaction mixture was stirred at room temperature for 24 h. After, the reaction was extracted with Et 2 O (3 × 50 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to give benzyl azides as pale yellow oils. The following azides were thus prepared (Table 3):

General Procedure for the Synthesis of Alkyl Azides (Method B)
To a stirred solution of 10.0 mmol alkyl halides (1.76 mL of octyl bromide, 1.78 mL of iso-octyl bromide, or 1.23 mL of bromocyclohexane) in 20 mL of DMF, 12.0 mmol (0.78 g) of sodium azide was added. The reaction mixture was stirred at 70 • C for 24 h in an oil bath. After, the reaction was extracted with Et 2 O (3 × 50 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure to give alkyl azides as pale yellow oils. The following azides were thus prepared (Table 4):

General Procedure for the Synthesis of Phenyl Azide
To a stirred solution of 0.46 mL aniline (5.0 mmol) in 25 mL 17% HCl solution at 0 • C, 0.51 g (7.5 mmol) of sodium nitrite in water (3 mL) was added. After stirring for 15 min, a solution of 0.32 g sodium azide (7.5 mmol) in water (3 mL) was carefully added. The reaction was left to stir for 1 h, followed by extraction with Et 2 O (3 × 30 mL). The combined organic layers were dried over Na 2 SO 4 , and carefully concentrated under reduced pressure to give phenyl azide as an orange oil.

General Procedure for the Synthesis of Prop-2-ynyl Diphenylphosphinate and Diethyl Prop-2-ynyl Phosphate
To a stirred solution of 10 mmol of diphenylphosphinic chloride (1.91 mL) or diethyl chlorophosphate (1.44 mL) in 10 mL of Et 2 O, 1.39 mL (10 mmol) of Et 3 N and 0.50 mL (10.0 mmol) of propargyl alcohol at 0 • C were added under a nitrogen atmosphere. The solution was left stirring at room temperature for 3-6 h and the reaction mixture obtained was passed through a 1 cm silica gel layer using Et 2 O. After evaporating the solvent, the products were obtained as white crystals (12a) or colorless oil (12b). The following products were thus prepared (Table 5):   1 mmol) of sodium ascorbate were added. The mixture was stirred at 60 • C for 10 min. The resulting solution was extracted with ethyl acetate (3 × 30 mL) and the combined organic layers were dried over Na 2 SO 4 . After evaporating the solvent, the crude product was purified by column chromatography using silica gel and dichloromethane/methanol 97:3 as the eluent. The following products were thus prepared:
Supplementary Materials: Supplementary data associated with this article are available online. Copies of 31 P, 1 H, and 13 C NMR spectra for all compounds synthesized are presented.