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

Article abstract of DOI:10.1021/acs.oprd.7b00274

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.

Full text of DOI:10.1021/acs.oprd.7b00274

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Full Paper
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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A green process for the preparation of bis(2,2,2ꢀtrifluoroethyl) methylphosphonate
,†
†
‡
†
Katalin Molnár,* László Takács, Ferenc Faigl, and Zsuzsanna Kardos
†
Prostaglandin Business Unit, Sanofi, Tó street 1ꢀ5, Budapest, Hꢀ1045, Hungary
Budapest University of Technology and Economics,
‡
Budafoki street 8, Budapest, Hꢀ1111. Hungary
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Purification
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KEYWORDS
flow chemistry, green process, methylphosphonate, microwave reactor, trifluoroethanol,
trifluoroethyl phosphonate
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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,βꢀunsaturated ketones and is also a
valuable potent flameꢀretardant additive. Preparation of bis(trifluoroethyl) methylphosphonate
was investigated by direct transesterification of dimethyl methylphosphonate with 2,2,2ꢀ
trifluoroethanol (further trifluoroethanol, TFE), being a wellꢀknown 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
1
StillꢀGennari's reagent used for the preparation of (Z)ꢀα,βꢀunsaturated esters as well as for the
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synthesis of Jin’s reagent used for the preparation of (Z)ꢀα,βꢀunsaturated ketones. Furthermore it
has been found that phosphonate 3 can serve as a flameꢀretardant additive in lithiumꢀion
3
batteries.
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 twoꢀstep procedure is
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used. First, dimethyl methylphosphonate (1) is converted with thionyl chloride or phosphorous
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pentachloride to methylphosphonic dichloride (2) followed by reacting the product with
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trifluoroethanol in the presence of triethylamine (Figure 1).
CF
3 2
CH OH
SOCl
2
or PCl
5
3
Et N
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 byꢀ
products 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
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A recent publication claimed that under microwave (MW) irradiation at 180ꢀ200 °C phosphinic
acids underwent direct esterification with alcohols having a longer alkyl chain (butyl, octyl,
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,10
dodecyl), providing 45ꢀ60% preparative yields, while with traditional heating
remained poor (12ꢀ15%).
conversion
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).
3 2
CF CH OH
3 2
CF CH OH
CF CH O
O
CF CH O
O
3
2
CH O
O
3
2
3
P
P
P
CF CH O
CH3
CH3
3
2
CH O
CH3
CH O
3
3
1
4
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)
1
4
3
0
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T
TFE
[
°C]
[equiv.]
Composition GC [area %]
1
75
00
00
5
5
99
99.5
95
0.1
0.5
5
0
0
0
2
2
10
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
Pressure
[
h]
max [bar]
Composition of the reaction mixture by GC [area %]
0
ꢀ
100
0
1
5
0
0
0
5
17
18
99
10
95
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*Additional 5 equiv. of trifluoroethanol was added
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Composition of reaction mixture
GC [area%]
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Reaction time [h]
Figure 3. Microwaveꢀassisted 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, 1,5ꢀdiazabicyclo[4.3.0]nonꢀ5ꢀene
(DBN)) or acidic catalyst (pꢀtoluenesulfonic acid, oꢀphosphoric 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 byꢀproducts. From the acidic catalysts listed, the use of
oꢀphosphoric acid resulted in the formation of several byꢀproducts. pꢀToluenesulfonic 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 pressureꢀproof batch reactor at maximum 10
bar pressure. In order to ensure not to exceed the pressure limit, esterification was performed at
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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.)
1
4
3
Overall
content
[m/m%]
Temperature
°C]
Time Pressure
[
[h]
max [bar]
Composition by GC [area %]
0
5
100
99
0
1
0
0
100
88
7
1
2
0
0
10
9
97
72
3
0
1
74
52
27
30
9
51
46
3
42
150
40
9
9
42
30
18
18
52
62
69
67
6
8
36
33
28
14
5
6
7
0
0
0
9
13
15
10
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Composition
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Overall content [m/m%]
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9
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10
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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.)
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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.
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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 nonꢀvolatile byꢀproducts. To determine the structure of the nonꢀ
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volatile products, after evaporation the residue was analysed by H, C and F NMR
spectroscopy. The byꢀproduct was found to be a mixture of phosphonic acid anhydrides (Figure
5). Note, however that these byꢀproducts are not useless, because they may serve as additives to
1
1
improve the mechanical properties of polymers.
5
6
7
Figure 5. Structure of phosphonic acid anhydride dimers (5ꢀ7) formed in the direct
transesterification of dimethyl methylphosphonate (1) with trifluoroethanol (TFE)
Formation of dimeric byꢀproducts 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 scaledꢀup and there is no limitation to batch size.
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ThalesNano’s Phoenix reactor was used in the experiments using a maximum temperature of
4
50 °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).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3
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8
9
0
1
2
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4
5
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8
9
0
Table 4. Direct transesterification of dimethyl methylphosphonate (1) with
trifluoroethanol (TFE) in a flow reactor
Contact
time
min]
1
4
3
Catalyst
[Yes / No]
Temperature
[°C]
Pressure
[bar]
Entry
Composition by GC area[%]
[
1
2
3
4
5
6
7
8
No
No
No
No
No
No
Yes
Yes
20
250
400
400
400
450
450
250
450
200
100
150
200
200
200
200
200
98.8
14.0
5.0
0.6
55.0
48.0
24.0
15.0
19.0
0
0
20
20
20
20
30
20
20
27.0
45.0
75.0
84.0
81.0
0
0.9
0.2
0.4
99.9
0.5
18.0
81.0
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
2
50°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
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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. Holdꢀup 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).
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Scaleꢀup 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) 2ꢀoxoalkylphosphonates, reagents for Zꢀselective
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HornerꢀWadsworthꢀEmmons reactions.
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
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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,
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fulfils atom economy and does not use hazardous chemicals or solvents.
EXPERIMENTAL SECTION
General information:
Progress of the reactions were monitored by GC analysis on an Agilent 6890 N, GCꢀMSD
instrument, using a DBꢀ624 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: MSꢀEI, 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 DBꢀ624 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
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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, 63ꢀ200 µm) using
hexane:ethyl acetate = 3:1 mixture as eluent.
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All the reagents were commercially available (SigmaꢀAldrich).
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 N in a closed vial in a CEM Discover
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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.
Scaleꢀup:
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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 reꢀused for further transesterification.
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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) 2ꢀoxoalkylphosphonates (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: katimolnar88@gmail.com; +36ꢀ30ꢀ725ꢀ3467; Fax: +36 1 505 2913; ORCID
ID: 0000ꢀ0003ꢀ0607ꢀ4169.
ACKNOWLEDGMENT
We thank SanofiꢀChinoin, Varga József and Pro Progressio Foundations for financial support
and Prof. M. Nógrádi for helpful discussions.
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ABBREVIATIONS
DBN, 1,5ꢀDiazabicyclo[4.3.0]nonꢀ5ꢀene; GC, gas chromatography; MW, microwave; PTS, pꢀ
toluenesulfonic acid; TFE, trifluoroethanol
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REFERENCES
(
1) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405ꢀ4408.
2) Yu, W.; Su, M.; Jin, Z. Tetrahedron Lett. 1999, 40, 6725ꢀ6728.
(
(3) Zeng, Z.; Jiang, X.; Wu, B.; Xiao, L.; Ai, X.; Yang, H.; Cao, Y. Electrochim. Acta, 2014,
29, 300ꢀ304.
1
(4) Maier, L. Phosphorus, Sulfur, 1990, 47, 465ꢀ470.
(5) Steinbach, T.; Alexandrino, E. M.; Wahlen, C.; Landfester, K.; Wurm, F. R.
Macromolecules, 2014, 47, 4884ꢀ4893.
(6) SinꢀRen, A. C.; Riggio, G.; Hopff, W. H.; Waser, P. G. J. Labelled Compd. Rad. 1988,
5, 483ꢀ495.
2
(7) Patois, C.; Savignac, P.; AboutꢀJaudet, E.; Collignon, N. Org. Synth. 1996, 73, 152ꢀ158.
(
8) Timperley, C. M.; Broderick, J. F.; Holden, I.; Morton, I. J.; Waters, M. J. Fluorine
Chem. 2000, 106, 43ꢀ52.
(9) Keglevich, G.; Kiss, N. Z.; Mucsi, Z.; Körtvélyesi, T. Org. Biomol. Chem. 2012, 10,
011ꢀ2018.
2
(10) Keglevich, G. Trends in Green Chemistry, 2015, 1, 1ꢀ6.
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(
(
11) Kins, C. F.; Brunklaus, G.; Spiess, H. W. Macromolecules, 2013, 46, 2067ꢀ2077.
12) http://thalesnano.com/phoenixꢀflowꢀreactor (accessed June 10, 2017)
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13) Molnár, K.; Takács, L.; Kádár, M.; Faigl, F.; Kardos, Zs. Tetrahedron Lett. 2015, 56,
4
877ꢀ4879.
(14) https://www.acs.org/content/acs/en/greenchemistry/whatꢀisꢀgreenꢀ
chemistry/principles/greenꢀchemistryꢀpocketꢀguides.html (accessed April 10, 2017)
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