A Green Process for the Preparation of Bis(2,2,2-trifluoroethyl

Article Cite This: Org. Process Res. Dev. 2017, 21, 1985−1989

pubs.acs.org/OPRD

A Green Process for the Preparation of Bis(2,2,2-trifluoroethyl) Methylphosphonate Katalin Molnár,*,† László Takács,† Ferenc Faigl,‡ and Zsuzsanna Kardos† †

Prostaglandin Business Unit, Sanofi, Tó street 1-5, Budapest, H-1045, Hungary Budapest University of Technology and Economics, Budafoki street 8, Budapest, H-1111, Hungary

‡

S Supporting Information *

ABSTRACT: Bis(trifluoroethyl) methylphosphonate is the starting material for the synthesis of Jin’s reagent. Jin’s reagent is widely used for the preparation of (Z)-α,β-unsaturated ketones and is also a valuable potent flame-retardant additive. Preparation of bis(trifluoroethyl) methylphosphonate was investigated by direct transesterification of dimethyl methylphosphonate with 2,2,2-trifluoroethanol (further trifluoroethanol, TFE), being a well-known weak nucleophile, using microwave and flow reactors. Direct transesterification was successful in a continuous flow reactor at 450 °C and 200 bar using a highly diluted reaction mixture. The product, bis(trifluoroethyl) methylphosphonate, was purified by column chromatography, and excess trifluoroethanol was recovered by distillation.

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INTRODUCTION Bis(trifluoroethyl) methylphosphonate (3) is an important starting material for the synthesis of Still−Gennari’s reagent1 used for the preparation of (Z)-α,β-unsaturated esters as well as for the synthesis of Jin’s reagent2 used for the preparation of (Z)-α,β-unsaturated ketones. Furthermore, it has been found that phosphonate 3 can serve as a flame-retardant additive in lithium-ion batteries.3 Because trifluoroethanol is a poor nucleophile, preparation of bis(trifluoroethyl) methylphosphonate (3) by transesterification of the readily available dimethyl methylphosphonate (1) fails under normal conditions. For the synthesis of bis(trifluoroethyl) methylphosphonate (3) most often a two-step procedure is used. First, dimethyl methylphosphonate (1) is converted with thionyl chloride4,5 or phosphorus pentachloride6 to methylphosphonic dichloride (2) followed by reacting the product with trifluoroethanol in the presence of triethylamine (Figure 1).7,8

RESULTS AND DISCUSSION A recent publication claimed that under microwave (MW) irradiation at 180−200 °C phosphinic acids underwent direct esterification with alcohols having a longer alkyl chain (butyl, octyl, dodecyl), providing 45−60% preparative yields, while with traditional heating conversion remained poor (12− 15%).9,10 These results and other advantages of the MW technique, e.g. the economy of small scale experiments (less than 1 mmol of starting material or 1 mL volume of reaction mixture in our case), high reproducibility, and extreme reaction conditions (up to 300 °C and 30 bar in our equipment), supported our decision. In screening experiments, dimethyl methylphosphonate (1) was reacted with 5 equiv of trifluoroethanol (TFE) at 175 and 200 °C, thereafter with 10 equiv of trifluoroethanol at 200 °C. Reactions were stopped after 5 h (t = 5 h), and the reaction mixtures were analyzed by GC (Figure 2, Table 1).

Figure 1. Preparation of bis(trifluoroethyl) methylphosphonate (3).

Figure 2. Direct transesterification of dimethyl methylphosphonate (1) with trifluoroethanol.

The process described above is highly negative from an environmental point of view. The reagents used (thionyl chloride or phosphorus pentachloride), the intermediates, and the byproducts arising from the procedure are highly toxic and/ or corrosive. To overcome the disadvantages of direct esterification, we set out to elaborate an environmentally friendly and scalable process for the preparation of our target compound, i.e. for bis(trifluoroethyl) methylphosphonate (3). © 2017 American Chemical Society

According to GC analysis after 5 h, conversions were modest and the desired product, i.e. bis(trifluoroethyl) methylphosphonate (3), was not present in the reaction mixtures. Only one methoxy group was replaced by trifluoroethanol forming the mixed ester, trifluoroethyl methyl methylphosphonate (4), in low yield. Received: August 15, 2017 Published: November 21, 2017 1985

DOI: 10.1021/acs.oprd.7b00274 Org. Process Res. Dev. 2017, 21, 1985−1989

Organic Process Research & Development

Article

process that required extreme reaction conditions. Under the conditions used, equilibrium was established after about 90 h. To accelerate the process, 0.05 equiv of a basic (KOH, 1,5diazabicyclo[4.3.0]non-5-ene (DBN)) or acidic catalyst (ptoluenesulfonic acid, o-phosphoric acid, sulfuric acid) was added and the reactions were run at 200 °C for 24 h. Basic catalysts were rejected because of low conversion and the formation of several byproducts. From the acidic catalysts listed, the use of o-phosphoric acid resulted in the formation of several byproducts. p-Toluenesulfonic acid and sulfuric acid accelerated the desired transformation, with the latter being the more effective catalyst. In the presence of sulfuric acid, dimethyl methyl phosphonate (1) disappeared in 20 h, while 68% of bis(trifluoroethyl) methylphosphonate (3) formed. Since our objective was to develop a scalable process for the preparation of bis(trifluoroethyl) methylphosphonate (3), experiments were to run in a pressure-proof batch reactor at maximum 10 bar pressure. In order to ensure not to exceed the pressure limit, esterification was performed at 150 and 175 °C in the presence of sulfuric acid in the MW reactor. Reactions were followed by GC analysis and were run until equilibrium was established. In the case of the experiments executed at 150 °C the overall content of the volatile components (overall content of 1, 4, and 3) was also determined by GC analysis (Table 3, Figure 4). Our experiments supported the catalytic effect of sulfuric acid. Equilibrium was established after about 60 h (1:4:3 = 18:69:13) at 150 °C and after 25 h (1:4:3 = 2:57:41) at 175 °C. However, quantitative analysis of the reaction mixture gave unexpected results. It revealed that the overall content of the three phosphonates was decreasing continuously with the progress of time, indicating the formation of nonvolatile byproducts. To determine the structure of the nonvolatile products, after evaporation the residue was analyzed by 1H, 13C, and 19F NMR spectroscopy. The byproduct was found to be a mixture of phosphonic acid anhydrides (Figure 5). Note, however that these byproducts are not useless, because they may serve as additives to improve the mechanical properties of polymers.11 Formation of dimeric byproducts pointed out that besides high pressure and high temperature, high dilution is also essential to achieve an acceptable yield of the target molecule

Table 1. Microwave-assisted Transesterification of Dimethyl Methylphosphonate (1) with Trifluoroethanol (t = 5 h) 1 T [°C]

TFE [equiv]

175 200 200

5 5 10

4

3

Composition GC [area %] 99 99.5 95

0.1 0.5 5

0 0 0

The next experiment was performed at 200 °C with 10 equiv of trifluoroethanol, and esterification was stopped when the starting material (1) disappeared and an equilibrium between 3 and 4 (Table 2, Figure 3) was established. Table 2. Microwave-assisted Transesterification of Dimethyl Methylphosphonate (1) with Trifluoroethanol (t = 5 h) 1

a

Time [h]

Pressure max [bar]

0 5 10 15 20 25 30 35 40 45 50 55 60 70a 80 90 100

− 17 18 19 19 18 18 19 17 16 15 15 16 17 16 15 15

4

3

Composition of the reaction mixture by GC [area %] 100 99 95 89 81 70 58 47 30 20 15 6 0 0 0 0 0

0 1 5 10 17 27 37 44 55 62 62 62 62 42 36 28 29

0 0 0 1 2 2 5 9 15 18 23 32 38 58 64 72 71

Additional 5 equiv of trifluoroethanol was added.

Composition of the reaction mixture revealed that direct transesterification of dimethyl methylphosphonate (1) with trifluoroethanol was feasible but was a prolonged and reversible

Figure 3. Microwave-assisted transesterification of dimethyl methylphosphonate (1) with 10 equiv of trifluoroethanol at 200 °C. 1986



Article

Table 3. Microwave-assisted Transesterification of Dimethyl Methylphosphonate (1) with Trifluoroethanol (TFE) in the Presence of Sulfuric Acid (0.05 equiv) 1 Temp [°C]

Time [h]

Pressure max [bar]

150

0 5 10 20 30 40 50 60 70 0 5 10 15 20 25 30 35

− 7 10 9 9 9 9 9 10 − 14 15 16 17 15 15 11

175

4

3

Composition by GC [area %] 100 99 97 72 51 42 30 18 18 100 61 20 8 5 2 2 1

0 1 3 27 46 52 62 69 67 0 37 72 70 63 57 56 56

0 0 0 1 3 6 8 13 15 0 2 8 22 32 41 42 43

Figure 5. Structure of phosphonic acid anhydride dimers (5−7) formed in the direct transesterification of dimethyl methylphosphonate (1) with trifluoroethanol (TFE).

Overall content [m/m%] 100 88 74 52 42 36 33 28 14 not determined

Table 4. Direct Transesterification of Dimethyl Methylphosphonate (1) with Trifluoroethanol (TFE) in a Flow Reactor 1 Catalyst Entry [Yes/No] 1 2 3 4 5 6 7 8

No No No No No No Yes Yes

Contact time [min]

Temp [°C]

Pressure max [bar]

20 20 20 20 20 30 20 20

250 400 400 400 450 450 250 450

200 100 150 200 200 200 200 200

4

3

Composition by GC [area %] 98.8 14.0 5.0 0.9 0.2 0.4 99.9 0.5

0.6 55.0 48.0 24.0 15.0 19.0 0 18.0

0 27.0 45.0 75.0 84.0 81.0 0 81.0

with trifluoroethanol requires extreme reaction conditions, i.e. both high temperature and high pressure since conversion was negligible when reactions were carried out at up to 250 °C temperature and up to 200 bar pressure. Conversion was higher at elevated temperature (entry 1 versus entry 4) and higher pressure (entry 2 versus entry 4). The best yields for bis(trifluoroethyl) methylphosphonate (3) were achieved working at both the highest temperature and pressure (entries 5 and 6) permitted by the apparatus. The residence time was also investigated, and 20 min were found to be sufficient to reach equilibrium (entry 5 versus entry 6); the role of the catalyst was almost insignificant (entry 5 versus entry 8). Scale-up was realized using an 8 mL loop of the continuous flow reactor to obtain bis(trifluoroethyl) methylphosphonate (3) at a 100 g scale. Dimethyl methyl phosphonate (1, 100 g) was dissolved in 100 equiv of trifluoroethanol (6.1 L), and the

(3). After having mapped all the parameters required for the direct transesterification, our attention turned to flow technology. With flow technology all the necessary requirements mentioned before, such as high pressure, high temperature, and high dilution, can be realized. Moreover, this method can be readily scaled-up and there is no limitation to batch size. ThalesNano’s Phoenix reactor12 was used in the experiments using a maximum temperature of 450 °C and pressures up to 200 bar. Reactions were performed with a 0.016 g/mL solution of dimethyl methylphosphonate (1), i.e. a 100 equiv excess of trifluoroethanol relative to 1. During the optimization process, the effects of temperature, pressure, and catalyst (0.05 equiv of sulfuric acid) were followed (Table 4). Experiments in the flow reactor demonstrated again that direct transesterification of dimethyl methylphosphonate (1)

Figure 4. Microwave-assisted transesterification of dimethyl methylphosphonate (1) at 150 °C in the presence of sulfuric acid (0.05 equiv) 1987



Article

solution was treated at 450 °C and 200 bar at a flow rate of 0.4 mL/min. The product (approximately 6.2 L) was collected and distilled at atmospheric pressure to recover 5.1 L of trifluoroethanol (yield of recovery: 84%, GC purity: 99%). The recovered trifluoroethanol could be reused without further purification. The residue was purified by column chromatography yielding 110 g (53%) of bis(trifluoroethyl) methylphosphonate (3). The procedure can be accelerated by using a larger, 16 mL loop and a flow rate of 0.8 mL/min by which the reaction time could be halved. Bis(trifluoroethyl) methylphosphonate (3) prepared by direct transesterification was successfully used for the preparation of bis(trifluoroethyl) 2-oxoalkylphosphonates, reagents for Z-selective Horner−Wadsworth−Emmons reactions.13

equipped with a pressure controller. Reactions were monitored by GC analysis. General Procedure for Reactions Performed in the Flow Reactor. Dimethyl methylphosphonate (1, 1.435 mL, 13.2 mmol) was dissolved in trifluoroethanol (100 mL, 1.32 mol), and the solution was fed continuously into the 4 mL loop of ThalesNano’s Phoenix reactor; the product was continuously removed. Reaction parameters were varied according to Table 4, and the reactions were monitored by GC analysis. Scale-up. Dimethyl methylphosphonate (1, 100.0 g, 0.8059 mol) was dissolved in trifluoroethanol (6.1 L, 80.79 mol). The solution was introduced into the flow reactor (flow rate: 0.4 mL/min, residence time: 20 min) using an 8 mL loop at 450 °C and 200 bar. The product was collected (6.20 L) and distilled giving 5.1 L of trifluoroethanol (yield of recovery: 84%, purity by GC: 99%), which can be reused for further transesterification. The residue was purified by column chromatography using a hexane/ethyl acetate = 3:1 mixture as eluent, giving 110 g (53%) of bis(trifluoroethyl) methylphosphonate (3), suitable for the preparation of bis(trifluoroethyl) 2-oxoalkylphosphonates (Jin’s reagents) without further purification.

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CONCLUSION The first direct transesterification method for the preparation of bis(trifluoroethyl) methylphosphonate (3) was developed reacting dimethyl methylphosphonate (1) with trifluoroethanol, a weak nucleophile. The reaction was carried out in a continuous flow reactor at 450 °C and 200 bar at high dilution. Excess trifluoroethanol was recovered by distillation, and the product, i.e. bis(trifluoroethyl) methylphosphonate (3), was purified by gravimetric column chromatography. The newly elaborated direct transesterification is a green process because it prevents waste, fulfills atom economy, and does not use hazardous chemicals or solvents.14

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.7b00274. Characterization of phosphonates (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; Phone: +36-30-725-3467; Fax: +36 1 505 2913.

EXPERIMENTAL SECTION General Information. The progress of the reactions were monitored by GC analysis on an Agilent 6890 N, GC-MSD instrument, using a DB-624 capillary column (60 m × 0.25 mm × 1.4 μm) with the following time program: 20 min at 35 °C, then heating with 10 °C/min to 260 °C, 3 min at 260 °C. Carrier gas was helium with a constant flow rate of 1.9 mL/min. A 1 μL aliquot of the reaction mixture was injected at 250 °C, split for sampling: 100 = 1. Detector: MS-EI, scan range: m/Z (29 → 400), Tsource: 230 °C, Tquad: 150 °C, Ttransfer line: 280 °C. The overall content of the phosphonates (1, 3, and 4) and the methanol content of the recovered trifluoroethanol were determined by quantitative GC analysis on an Agilent 6890 N instrument, using a DB-624 capillary column (60 m × 0.25 mm × 1.4 μm) with the following time program: 10 min at 30 °C, then heating with 25 °C/min to 260 °C, 6 min at 260 °C. Helium was the carrier gas with a constant flow rate of 2.3 mL/ min. A 1 μL aliquot of the reaction mixture was injected at 200 °C, split for sampling: 100 = 1. Detector: FID at 300 °C. Column chromatography was performed on Merck silica gel (Kieselgel 60, 63−200 μm) using a hexane/ethyl acetate = 3:1 mixture as eluent. All the reagents were commercially available (SigmaAldrich). General Procedure for the Direct Transesterification Reactions. General Procedure for Reactions Carried out in the Microwave Reactor. A solution of dimethyl methylphosphonate (1, 140 μL, 1.31 mmol) and trifluoroethanol (989 μL, 13.1 mmol) was heated at 150, 175, or 200 °C under N2 in a closed vial in a CEM Discover Microwave Synthesis System

ORCID

Katalin Molnár: 0000-0003-0607-4169 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Sanofi-Chinoin, Varga József and Pro Progressio Foundations for financial support and Prof. M. Nógrádi for helpful discussions.

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ABBREVIATIONS DBN, 1,5-Diazabicyclo[4.3.0]non-5-ene; GC, gas chromatography; MW, microwave; PTS, p-toluenesulfonic acid; TFE, trifluoroethanol

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REFERENCES

(1) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405−4408. (2) Yu, W.; Su, M.; Jin, Z. Tetrahedron Lett. 1999, 40, 6725−6728. (3) Zeng, Z.; Jiang, X.; Wu, B.; Xiao, L.; Ai, X.; Yang, H.; Cao, Y. Electrochim. Acta 2014, 129, 300−304. (4) Maier, L. Phosphorus, Sulfur Silicon Relat. Elem. 1990, 47, 465− 470. (5) Steinbach, T.; Alexandrino, E. M.; Wahlen, C.; Landfester, K.; Wurm, F. R. Macromolecules 2014, 47, 4884−4893. (6) Sin-Ren, A. C.; Riggio, G.; Hopff, W. H.; Waser, P. G. J. Labelled Compd. Radiopharm. 1988, 25, 483−495. (7) Patois, C.; Savignac, P.; About-Jaudet, E.; Collignon, N. Org. Synth 1996, 73, 152−158.

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(8) Timperley, C. M.; Broderick, J. F.; Holden, I.; Morton, I. J.; Waters, M. J. Fluorine Chem. 2000, 106, 43−52. (9) Keglevich, G.; Kiss, N. Z.; Mucsi, Z.; Körtvélyesi, T. Org. Biomol. Chem. 2012, 10, 2011−2018. (10) Keglevich, G. Trends in Green Chemistry 2015, 1, 1−6. (11) Kins, C. F.; Brunklaus, G.; Spiess, H. W. Macromolecules 2013, 46, 2067−2077. (12) http://thalesnano.com/phoenix-flow-reactor (accessed June 10, 2017). (13) Molnár, K.; Takács, L.; Kádár, M.; Faigl, F.; Kardos, Zs. Tetrahedron Lett. 2015, 56, 4877−4879. (14) https://www.acs.org/content/acs/en/greenchemistry/what-isgreen-chemistry/principles/green-chemistry-pocket-guides.html (accessed April 10, 2017).

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A Green Process for the Preparation of Bis(2,2,2-trifluoroethyl

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