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

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A green process for the preparation of bis(2,2,2-trifluoroethyl) methylphosphonate Katalin Molnar, Laszlo Takacs, Ferenc Faigl, and Zsuzsanna Kardos Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00274 • Publication Date (Web): 21 Nov 2017 Downloaded from http://pubs.acs.org on November 22, 2017

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Organic Process Research & Development

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

ACS Paragon Plus Environment

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TOC Figure

Purification Flow reactor


2

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KEYWORDS flow chemistry, green process, methylphosphonate, microwave reactor, trifluoroethanol, trifluoroethyl phosphonate

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 2,2,2trifluoroethanol (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

methylphosphonate

(3)

is by

a

poor

nucleophile,

transesterification

of

preparation the

readily

of

bis(trifluoroethyl)

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 phosphorous pentachloride6 to methylphosphonic dichloride (2) followed by reacting the product with trifluoroethanol in the presence of triethylamine (Figure 1).7,8

CF3CH2OH

SOCl2 or PCl5

Et3N 1

2

3

Figure 1. Preparation of bis(trifluoroethyl) methylphosphonate (3) The process described above is highly negative from an environmental point of view. Both the reagents used (thionyl chloride or phosphorous 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


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scalable process for the preparation of our target compound, i.e. for bis(trifluoroethyl) methylphosphonate (3). 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 heating9,10 conversion remained poor (12-15%). These results and other advantages of 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 equivalents of trifluoroethanol (TFE) at 175 °C and 200 °C, thereafter with 10 equivalents of trifluoroethanol at 200 °C. Reactions were stopped after 5 hours (t = 5h) and the reaction mixtures analysed by GC (Figure 2, Table 1).

O

CH3 O

CH3

1

O

CF3CH2O

CF3CH2OH

CH3

CH3 O

O

CF3 CH2 O

P

P

P CH3 O

CF3CH2OH

4

CH3

CF3 CH2 O

3

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


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Table 1. Microwave (MW) assisted transesterification of dimethyl methylphosphonate (1) with trifluoroethanol (t = 5h)

T [°C]

TFE [equiv.]

1

4

3

175

5

99

0.1

0

200

5

99.5

0.5

0

200

10

95

5

0

Composition GC [area %]

According to GC analysis after 5 hours 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. The next experiment was performed at 200 °C with 10 equivalents 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 = 5h)

1

4

3

Time [h]

Pressure max [bar]

0

-

100

0

0

5

17

99

1

0

10

18

95

5

0

Composition of the reaction mixture by GC [area %]


6

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15

19

89

10

1

20

19

81

17

2

25

18

70

27

2

30

18

58

37

5

35

19

47

44

9

40

17

30

55

15

45

16

20

62

18

50

15

15

62

23

55

15

6

62

32

60

16

0

62

38

70*

17

0

42

58

80

16

0

36

64

90

15

0

28

72

100

15

0

29

71

*Additional 5 equiv. of trifluoroethanol was added


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Composition of reaction mixture GC [area%]

1

4

3

100 90 80 70 60 50 40 30 20 10 0 0

10

20

30

40

50

60

70

80

90

100

Reaction time [h]

Figure 3. Microwave-assisted transesterification of dimethyl methylphosphonate (1) with 10 equiv. of trifluoroethanol at 200 °C Composition of the reaction mixture revealed that direct transesterification of dimethyl methylphosphonate (1) with trifluoroethanol was feasible but was a prolonged and reversible 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, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)) or acidic catalyst (p-toluenesulfonic acid, o-phosphoric acid, sulphuric 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 by-products. From the acidic catalysts listed, the use of o-phosphoric acid resulted in the formation of several by-products. p-Toluenesulfonic acid and sulphuric acid accelerated the desired transformation the latter being the more effective catalyst.


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In the presence of sulphuric 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 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 sulphuric 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). Table 3. Microwave (MW) assisted transesterification of dimethyl methylphosphonate (1) with trifluoroethanol (TFE) in the presence of sulphuric acid (0.05 equiv.)

Temperature [°C]

Time [h]

Pressure max [bar]

1

4

3

Composition by GC [area %] 0

150

Overall content [m/m%]

100

0

0

100

5

7

99

1

0

88

10

10

97

3

0

74

20

9

72

27

1

52

30

9

51

46

3

42

40

9

42

52

6

36

50

9

30

62

8

33

60

9

18

69

13

28

70

10

18

67

15

14


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0

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100

0

0

5

14

61

37

2

10

15

20

72

8

15

16

8

70

22

20

17

5

63

32

25

15

2

57

41

30

15

2

56

42

35

11

1

56

43

not determined

175

Composition by GC [area %]

Overall content [m/m%]

1

4

3

100 90 80 70 60 50 40 30 20 10 0 0

10

20

30

40

50

60

70

Reaction time [h]

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


10

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Our experiments supported the catalytic effect of sulphuric 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 non-volatile by-products. To determine the structure of the nonvolatile products, after evaporation the residue was analysed by 1H,

13

C and

19

F NMR

spectroscopy. The by-product was found to be a mixture of phosphonic acid anhydrides (Figure 5). Note, however that these by-products are not useless, because they may serve as additives to improve the mechanical properties of polymers.11

5

6

7

Figure 5. Structure of phosphonic acid anhydride dimers (5-7) formed in the direct transesterification of dimethyl methylphosphonate (1) with trifluoroethanol (TFE) Formation of dimeric by-products pointed out that beside high pressure and high temperature, high dilution is also essential to achieve an acceptable yield of the target molecule (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.


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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 related to 1. During the optimization process, effects of temperature, pressure and catalyst (0.05 equiv. of sulphuric acid) was followed (Table 4). Table

4.

Direct

transesterification

of

dimethyl

methylphosphonate

(1)

with

trifluoroethanol (TFE) in a flow reactor

Entry

Catalyst [Yes / No]

1

No

Contact time [min] 20

2

No

3

1

4

3

Temperature [°C]

Pressure [bar]

250

200

98.8

0.6

0

20

400

100

14.0

55.0

27.0

No

20

400

150

5.0

48.0

45.0

4

No

20

400

200

0.9

24.0

75.0

5

No

20

450

200

0.2

15.0

84.0

6

No

30

450

200

0.4

19.0

81.0

7

Yes

20

250

200

99.9

0

0

8

Yes

20

450

200

0.5

18.0

81.0

Composition by GC area[%]

Experiments in the flow reactor demonstrated again that direct transesterification of dimethyl methylphosphonate (1) with trifluoroethanol requires extreme reaction conditions, i.e. both high temperature and high pressure since conversion was negligible when reactions were carried 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). Best yields for


12

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bis(trifluoroethyl) methylphosphonate (3) were achieved working both at the highest temperature and pressure (Entries 5 and 6) permitted by the apparatus. Hold-up time was also investigated and 20 min was found to be sufficient to reach equilibrium (Entry 5 versus. Entry 6)and the role of the catalyst was almost indifferent (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 10 g scale. Dimethyl methyl phosphonate (1, 100 g) was dissolved in 100 equiv. of trifluoroethanol (6.1 L) and the solution was treated at 450 °C and 200 bar at a flow rate of 0.4 mL/min. The product (approx. 6.2 L) was collected and distilled at atmospheric pressure to recover 5.1 L 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%) 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 CONCLUSION


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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, fulfils atom economy and does not use hazardous chemicals or solvents.14 EXPERIMENTAL SECTION General information: 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 x 0.25 mm x 1.4 µm) with the 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 constant flow rate of 1.9 mL/min. 1 µl 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. 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 x 0.25 mm x 1.4 µm) with the time program: 10 min at 30 °C, then heating with 25 °C/min to 260 °C, 6 min at 260°C. with helium as carrier gas with


14

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constant flow rate of 2.3 mL/min. 1 µl 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 hexane:ethyl acetate = 3:1 mixture as eluent. All the reagents were commercially available (Sigma-Aldrich).

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 °C, 175 °C or 200 °C under N2 in a closed vial in a CEM Discover Microwave Synthesis System 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, and the product was continuously removed. Reaction parameters were varied according to Table 4 and the reactions were monitored by GC analysis. Scale-up:


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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: 0.4mL/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 re-used for further transesterification. The residue was purified by column chromatography using a hexane: ethyl acetate = 3:1 mixture as eluent, giving 110 g (53%) bis(trifluoroethyl) methylphosphonate (3), suitable for the preparation of bis(trifluoroethyl) 2-oxoalkylphosphonates (Jin’s reagents) without further purification. ASSOCIATED CONTENT Supporting Information. The following files are available free of charge. Supporting Information (Characterization of phosphonates (PDF))

AUTHOR INFORMATION Corresponding author *Katalin Molnár: [email protected]; +36-30-725-3467; Fax: +36 1 505 2913; ORCID ID: 0000-0003-0607-4169. ACKNOWLEDGMENT 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, ptoluenesulfonic acid; TFE, trifluoroethanol 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, 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. Rad. 1988, 25, 483-495. (7) Patois, C.; Savignac, P.; About-Jaudet, E.; Collignon, N. Org. Synth. 1996, 73, 152-158. (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.


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(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-is-greenchemistry/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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