Fluorodecarboxylation: Synthesis of aryl trifluoromethyl ethers (ArOCF3) and thioethers (ArSCF3)

Accepted Manuscript Title: Fluorodecarboxylation: Synthesis of Aryl Trifluoromethyl Ethers (ArOCF3 ) and Thioethers (ArSCF3 ) Authors: Sankarganesh Krishanmoorthy, Simon D. Schnell, Huong Dang, Fang Fu, G.K. Surya Prakash PII: DOI: Reference:

S0022-1139(17)30257-9 http://dx.doi.org/doi:10.1016/j.jfluchem.2017.07.017 FLUOR 9025

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FLUOR

Received date: Revised date: Accepted date:

6-6-2017 26-7-2017 27-7-2017

Please cite this article as: Sankarganesh Krishanmoorthy, Simon D.Schnell, Huong Dang, Fang Fu, G.K.Surya Prakash, Fluorodecarboxylation: Synthesis of Aryl Trifluoromethyl Ethers (ArOCF3) and Thioethers (ArSCF3), Journal of Fluorine Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.07.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Fluorodecarboxylation: Synthesis of Aryl Trifluoromethyl Ethers (ArOCF3) and Thioethers (ArSCF3) Sankarganesh Krishanmoorthy, Simon D. Schnell, Huong Dang, Fang Fu, G. K. Surya Prakash* Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661, United States E-mail: [email protected]

Dedicated to Prof. Antonio Togni on the occasion of receiving the ACS Award for Creative Work in Fluorine Chemistry

1

Graphical Abstract Fluorodecarboxylation of aryloxydifluoroacetic acid (ArSCF2CO2H) and arylmercaptodifluoroacetic acid (ArSCF2CO2H) towards ArXCF3 (X= O, S) using silver (I) salts in the presence of Selectfluor in a biphasic system with trifluoroacetic acid additive is discussed.

2

Highlights  Easy preparation of starting materials from commercially available compounds.  Synthesis of aryl trifluoromethyl ethers and aryl trifluoromethyl thioethers.  Short reaction times and ambient temperatures.

3

Abstract Fluorodecarboxylation of aryloxydifluoroacetic acid (ArOCF2CO2H) and arylmercaptodifluoroacetic acid (ArSCF2CO2H) towards ArXCF3 (X= O, S) using silver (I) salts in the presence of Selectfluor in a biphasic system with trifluoroacetic acid additive is discussed.

1. Introduction Synthetic method development for the construction of -XCF3 (X = O, S) groups is an active area of research, as these moieties with high lipophilic index (Figure 1) promise to positively impact the pharmacokinetic properties of biologically active molecules [1]. Particularly, development in the area of aryl trifluoromethyl ethers and thioethers has been very limited, though examples of such scaffolds are already in the marketed drugs. Groups

SCF3

> OCF3

> CF3

> CH3

> OCH3

Hyrophobicity (Π)

1.44

1.04

0.88

0.56

-0.02

4

Figure 1 SCF3 and OCF3 groups’ hydrophobicity and examples in the medical field. Common synthetic approaches include (Scheme 1) 1) trifluoromethylation of phenols

and

thiophenols

[ 2 ],

2)

nucleophilic

trifluoromethoxylation

or

trifluoromethylthiolation of R-X compounds [3] and 3) fluoride exchange with ArXCY3 (X =O, S; Y= Cl, Br, I) [4]. 1) CF3-X (X = O, S) bond formation: trifluoromethylation of thiols and alcohols

R

X

[CF 3]+ R

H

X

CF3

2) X-C (X = O, S) bond formation: Trifluoromethoxylation and trifluoromethylthiolation R-Z

- YCF 3

R

Y

CF3

3) Fluorination: C-F bond formation Ar

X

CY3

X = S, O; X3 = Cl3, F 2Br

Ar

X

F F C F

Scheme 1 Methods for the construction of XCF3 (X = O, S) groups The C-F bond forming method towards -XCF3 is a promising approach for

18

F

labeling, which has become a powerful tool in PET imaging studies of biological systems [5]. However, the short half-life (110 minute) of 18F isotope demands that it is introduced at the late stage of the drug synthesis. Recently, Gouverneur et al. demonstrated silver mediated 18F- exchange of bromo/chloro difluoromethyl arylethers (ArOCF2X; X = Cl or Br) [6]. Following the fluorodecarboxylation of aliphatic carboxylic acids protocol of Li and co-workers [ 7 ], Gouverneur et al. demonstrated fluorodecarboxylation of ArCF2CO2H in the presence of

18

F-Selectfluor and silver (I) salts [8]. Sammis and co-

workers demonstrated photo-induced fluorodecarboxylation for the preparation of aryl mono and difluoromethyl ethers [9]. However, such a light induced decarboxylative fluorination of ArOCF2CO2H to ArOCF3 has been reported to be ineffective [10]. The synthetic pathway is believed to follow an arene excitation/oxidation pathway. Alternatively, we hypothesized that aryloxydifluoromethylene radical generated by a transition metal mediated oxidative decarboxylation (via carboxyl radical) could react with electrophilic fluorinating agents such as Selectfluor. As the silver catalysis in this area has been shown to be effective, we began our investigation with catalytic amounts of silver salts for fluorodecarboxylation of aryloxydifluoroacetic acids. We presented our preliminary results of fluorodecarboxylation of ArXCF2CO2H (X = O, S) at the 251th 5

ACS national meeting [11]. During the preparation of our manuscript, Hartwig et al. reported decaboxylative fluorination approach using AgF3 for the preparation of aryl trifluoromethyl ethers [12], Hu and co-workers presented their results using Selectfluor and Ag(I) under superacidic conditions [13], and recently Sammis et al. used XeF2 to accomplish ArOCF3 preparation [ 14 ]. In this communication, the results of fluorodecarboxylation of aryldifluoroacetic acids and aryl difluorthioacetic acids using Ag(I) in the presence of Selectfluor in a biphasic medium with trifluoroacetic acid and phosphoric acid as additives are summarized. 2. Results and discussion 2.1 Fluorodecarboxylation of ArOCF2CO2H 2.1.1. Preparation of ArOCF2CO2H The precursors, ArOCF2CO2H, can be easily prepared from inexpensive starting materials, namely, phenols and chlorodifluoroacetic acid in high yields [15]. However, the preparation of electron-withdrawing substituted (4-NO2, 3,5-ditrifluoromethyl-) phenols seemed to be rather challenging under these reaction conditions.

Table 1 Preparation of ArOCF2CO2H.a

6

a

Isolated yields

2.1.2. Reaction screening for fluorodecarboxylation of ArOCF2CO2H The fluorodecarboxylation was investigated with phenoxydifluoroacetic acid (1a) as a model substrate (Table 2). Under the reported successful fluorodecarboxylation conditions, AgX in acetone/water mixture at 55 C, 1 hour, 1a produced the desired product (2a) in 3% yield (Table 2, Entry 1) and protodecarboxylated difluoromethyl ether (5) in 36% yield. However, 48% of the starting material remained unreacted. Table 2 Screening of conditions and optimization.a

Entry

Catalyst

Solvent (ratio)

Time (h)

2a (%)

5 (%)

1

AgNO3

Acetone/H2O (10:1)

1

3

36

2

AgNO3

H2O

1

26

0

3

AgNO3

Benzene/H2O (1:1)

1

55

0

4

AgNO3

DCM/H2O (1:1)

1

31

traces

5

AgNO3

Hexane/H2O (1:1)

1

33

traces

6

AgNO3

EtOAc/H2O (1:1)

1

11

traces

b

7

AgNO3

DCM/H2O (39:1)

1

8%

traces

8

AgNO3

DCM/H2O (39:1)

1

46

traces

9

AgBF4

DCM/H2O (39:1)

1

62

traces

10

AgF

DCM/H2O (39:1)

1

51

traces

11

AgOAc

DCM/H2O (39:1)

1

44

traces

12

Ag2CO3

DCM/H2O (39:1)

1

38

traces

13

AgOTf

DCM/H2O (39:1)

1

66

traces

c

14

AgOTf

DCM/H2O/H3PO4

1

90

traces

c

15

AgOTf

DCM/H2O/TFA

1

65

traces

AgOTf

DCM/H2O/H3PO4

10 min

85

traces

c, d

a

16

The reactions were carried out on a 0.25 mmol scale with 2 equiv Selectfluor, 20 mol%

of catalyst. The yields were determined by

19

F NMR using hexafluorobenzene as an

7

internal standard. bK3PO4 (1.1 equiv) was used as an additive. c9:1 DCM to water ratio with 4 equiv of additive (H3PO4 or TFA) was used. dReaction was carried out at 85 C under microwave irradiation. No reaction was observed in acetone and DMF, and greater than 95% of starting material remained unreacted. However, when the reaction was performed in water, the reaction proceeded to completion with an increase in the yield of trifluoromethyl phenyl ether to 26% (Table 2, Entry 2) and no unreacted starting material was observed. Our extensive effort to improve the yield in water was fruitless. We speculated that the decomposition of the starting material could be controlled by a biphasic reaction system, wherein the organic layer can serve as a shield for the starting material and the product from the reactive species in the aqueous phase. When benzene/water (1:1) was employed as a solvent system, the product conversion went up to 55%, only trace of difluoromethyl ether was observed (Table 2, Entry 3). However, a new signal appeared at -65.2 ppm (18%) in the

19

F NMR, which was confirmed from the literature data and by a GC-MS

analysis to be PhOCF2Ph. Though the signal around -65 ppm was minimal in chlorobenzene, trifluorotoluene and toluene, no improvement in the yield of the desired product was observed. Other biphasic systems such as DCM (dichloromethane), EtOAc and hexane with water produced conversion between 20-35% (Table 2, Entry 4-6). For further investigation of the biphasic system, DCM/water seemed to be the best. A close examination of the water/DCM ratio showed that water was absolutely necessary for the desired transformation. When a minimal amount of water (1:39) was used, the conversion seemed to improve from 30% to 46% (Table 2, Entry 8). The basic nature of the system reduced the formation of desired product, which could be attributed to the reactivity of the anion towards Selectfluor and increase in the amount of aryloxydifluoroacetate in the aqueous system. When a little over an equivalent of K3PO4 was added to the reaction mixture with AgNO3 as a catalyst, the amount of the product significantly diminished (8%) (Table 2, Entry 7). With this solvent system, other silver salts were investigated showing a following trend (Table 2, Entry 8-13): AgOTf (66%) > AgBF4 (62%) > AgF (51%) > AgNO3 (46%) > AgOAc (44%) > Ag2CO3 (38%). Therefore, further investigations were carried out with AgOTf. Previously, in a similar system, Li et al found that when TFA (trifluoroacetic acid) or H3PO4 used as additives, the reaction yield

8

seemed to improve. 16 Similarly, when H3PO4 was used as an additive for the present transformation, the desired product yield appeared to increase. After careful optimization of the solvent/additive ratios, DCM/water (9:1) as a solvent and 4 equivalents of additive provided 90% of the desired product in an hour at 55 C (Table 2, Entry 14), whereas in the presence of TFA, 65% of the product was observed (Table 2, Entry 15). A short reaction time (30 min) or less than 20 mol% of AgOTf use lowered the product yield. Interestingly, the reaction proceeded at room temperature over 12 hours to provide 75% of the desired product. For the PET imaging studies, a short reaction time for the fluorination is desired as the

18

F half-life is 110 min. In this regard, 85% of product

formation was observed at 85 C in 10 min under microwave irradiation (Table 2, Entry 16). 2.1.3. Substrate scope of the optimized conditions Table 3 Substrate scope.a

a

a and b represent the yields determined by

19

F NMR using hexafluorobenzene as an

internal standard, when TFA and H3PO4 were used as additives, respectively. The optimized condition was tested for the substrates shown in Table 3. The tertbutyl group substituted acids performed poorly in the presence of phosphoric acid (2b and 2c, Table 3), which was attributed to their poor solubility. When phosphoric acid was replaced with TFA, 53% and 61% conversions, respectively, were obtained. Consequently, all the substrates were studied in the presence of TFA as well as H3PO4. 9

The 2,6-dimethyl phenoxy difluoroacetic acid showed trace of the product (2d) in the 19F NMR. Halogen substituted substrates provided yields in the range of 19-60% (2f-j). In the case of electron-donating methoxy group, trace of ring fluorination was seen in the 19

F NMR. With the napthyl (2k) and 4-phenyl (2l) substrates, brown coloration of the

reaction mixture was observed and no fluodecarboxylated product was detected in the 19F NMR. 2.2 Fluorodecaroxboxylation of ArSCF2CO2H 2.2.1. Preparation of ArSCF2CO2H The arylmecraptodifluoromethylacetic acids are easily accessible from the corresponding thiols and chlorodifluoroacetic acid.The thiophenols under reflux in the presence of NaH and ClCF2COH in dioxane easily delivered the ArSCF2CO2H compounds (Table 4). Table 4 Preparation of ArSCF2CO2H.a

a

Isolated yields

2.2.2. Reaction screening and optimization for fluorodecarboxylation of ArSCF2CO2H When the previously reported conditions were employed for the decarboxylation, we found that the reactions proceeded at a slower rate (Table 5, entry 1) and increasing the reaction time to 1 hour and 30 min led to the completion of the reaction (Table 5, entry 2). Since the TFA additive performed well with the previously discussed system, the present reaction condition was optimized with TFA. Increasing the reaction temperature increased the rate of the reaction (Table 5, entry 3 & 4) with significant

10

product formation. For example, at 100 C under microwave conditions, 73% product formation was observed in just 2 min. Table 5 Conditions screening and optimization.a

Entry

a

Catalyst (20 mol%))

[F]+

Solvent

Time (h)

T (C)

4d (%)

1

AgOTf

Selectfluor (2.0 equiv)

DCM/H2O

1

55

78

2

AgOTf

Selectfluor (2.0 equiv)

DCM/H2O

1.5

55

92

b

3

AgOTf

Selectfluor (2.0 equiv)

DCM/H2O

15 min

75 (mw)

76

b

4

AgOTf

Selectfluor (2.0 equiv)

DCM/H2O

2 min

100 (mw)

73

The reactions were carried out on a 0.25 mmol scale with 2 equiv Selectfluor and 20

mol% of catalyst using TFA (4 equiv) as an additive. The yields were determined by 19F NMR using hexafluorobenzene as an internal standard. bCarried out under microwave irradiation. 2.2.3. Substrate scope of the optimized conditions Under the present conditions, electron-donating methyl groups performed well (4b). However, the substrate with –OMe group produced lower yield of the product (4g). 19

F NMR of the reaction mixture showed evidence of direct ring fluorination and

oxidation of the sulfur atom. Halogen containing substrates (4c-f) produced excellent yields. Electron-withdrawing bistrifluoromethyl containing substrate produced moderate yield of the product (4h). Oxidation of sulfur was observed in the absence of the silver salt. Table 6 Substrate scope.a

11

a

Yields in the parentheses were determined by 19F NMR using hexafluorobenzene as an

internal standard. 2.3. Mechanism Control experiments carried out without the silver salt or Selectfluor yielded no product. Based on the observation of PhCF2OPh (Scheme 2) and the decrease in the product yield, when the reaction was carried out in the presence of air, we propose that the reaction proceeds via PhOCF2 radical produced by higher oxidation state silver species [17]. Compound 6 is more likely formed as a result of the PhOCF2 radical reaction with the solvent benzene. Similar reaction pathway is likely prevalent in the case of fluorodecarboxylation of arylmercaptodifluoroacetic acids.

Scheme 2. Fluorodecarboxylation in benzene. 3. Conclusions The work presented in this communication, though of limited substrate scope, is one of the first examples of fluorodecarboxylation of aryloxydifluoroacetic acids and arylmercaptodifluoroacetic acids to provide aryl trifluoromethyl ethers and aryl trifluoromethyl thioethers, respectively. We were able to demonstrate that the ArXCF2CO2H (X = O, S) are useful substrates in realizing ArXCF3 compounds by oxidative fluorodecarboxylation approach. Therefore, we believe that the ease of preparation and commercial availability of substrates will encourage researchers to investigate other metal mediated fluorodecarboxylation processes. Further, oxidative 12

decarboxlative fluorination using fluoride is the next key direction to take in this area as the techniques are very well developed for the generation of 18F anion using a cyclotron. Such a development will be useful in late-stage fluorination and will be a powerful tool in PET imaging studies. 4. Experimental Section 4.1. General information 1

H,

13

C and

19

F NMR spectra were recorded on Varian 500 MHz or 400 MHz

NMR spectrometers. 1H NMR chemical shifts were determined relative to the signal of a residual protonated solvent, CDCl3 (δ 7.26) or DMSO-d6 (δ 2.5).

13

C NMR chemical

shifts were determined relative to the 13C signal of solvent, CDCl3 (δ 77.16) or DMSO-d6 (δ 39.52).

19

F NMR chemical shifts were determined relative to CFCl3 as an internal

standard (δ 0.0). HRMS data was obtained from the University of Illinois UrbanaChampaign’s mass spectrometry laboratory. Typically, all mixtures were prepared and the reactions were carried out under an inert atmosphere in sealed microwave vials. Unless otherwise mentioned, all the reactants, reagents and solvents were purchased from commercial sources. 4.2. Preparation of aryloxydifluoroacetic acid Under inert atmosphere (N2, Schlenk flask), to a suspension of sodium hydride (8.3 g, 346 mmol, 3.6 equiv) in freshly distilled dioxane (125 mL), phenols (144 mmol, 1.5 equiv) were introduced slowly (exothermic reaction and evolves H2 gas). To this mixture, the chlorodifluoroacetic acid (8.1 mL, 96.0 mmol, 1.0 equiv) was slowly added at 0 °C. Then, the solution was immersed in a temperature controlled oil bath to achieve a gentle reflux. The reaction progress was monitored by19F NMR. After 20-24 h, the acid was completely consumed and the mixture was concentrated in a rotary evaporator. The residue was dissolved in water (400 mL), and acidified with conc. HCl to reach pH = 1. Subsequenlty, the mixture was basified with NaHCO3 to reach pH = 8, and washed with DCM to remove the unreacted phenol. The solution was then acidified to pH = 1 and extracted with DCM (4 x 200 mL). After drying the combined organic layer with MgSO4 and filtration, the solvent was removed by rotary evaporation to obtain the compounds listed in Table 2.

13

4.2.1. 2,2–difluoro–2–phenoxyacetic acid (1a) 1

H NMR (DMSO-d6) δ 7.48–7.42 (m, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 7.7 Hz,

2H); 13C–NMR (DMSO-d6) δ 160.6 (t, J = 39.4 Hz), 149.2, 130.0, 126.4, 121.2, 114.2 (t, J = 271.9 Hz) 19F NMR (DMSO-d6) δ –75.77; HRMS (ESI): calc. for C8H5O3F2 [M-H]: 187.0207; found: 187.0208. 4.2.2. 2–(4–(tert–butyl)phenoxy)–2,2-difluoroacetic acid (1b) Melting point: 67–68 °C; 1H NMR (DMSO-d6) δ 7.46 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 1.27 (s, 9H);

13

C NMR (DMSO-d6) δ 160.6 (t, J = 39.5 Hz), 148.8, 146.8,

126.7, 120.7, 114.2 (t, J = 271.4 Hz), 34.2, 31.1; 19F NMR (DMSO-d6) δ –75.73; HRMS (ESI): Calculated for C12H13O3F2 [M-H]: 243.0833; found: 243.0835. The obtained analytical data is consistent with the values found in the literature [18]. 4.2.3. 2-(3-(tert-butyl)phenoxy)-2,2-difluoroacetic acid (1c) 1

H NMR (399 MHz, DMSO-d6) δ 7.39 – 7.28 (m, 2H), 7.16 (d, J = 2.7 Hz, 1H), 7.03

(ddd, J = 7.7, 2.7, 1.4 Hz, 1H), 1.27 (d, J = 1.1 Hz, 9H); 19F NMR (376 MHz, DMSO-d6) δ -75.66; HRMS (ESI): Calculated for C12H13O3F2 [M-H]: 243.0833; found: 243.0833. 4.2.4. 2–(2,6–dimethylphenoxy)–2,2-difluoroacetic acid (1d) 1

H NMR (DMSO-d6) δ 7.15–7.09 (m, 3H), 2.24 (s, 6H); 13C NMR (DMSO-d6) δ 160.9 (t,

J= 39.7 Hz), 146.3, 132.0, 129.1, 126.6, 114.9 (t, J = 273.4 Hz), 16.6; 19F NMR (DMSOd6) δ –74.14; HRMS (ESI): Calculated for C10H9O3F2 [M-H]: 215.0520; found: 215.0519. 4.2.5. 2,2–difluoro–2–(4–methoxyphenoxy)acetic acid (1e) 1

H NMR (DMSO-d6) δ 7.65 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 2.08 (s, 3H); C NMR (DMSO-d6) δ 160.7 (t, J = 39.5 Hz), 157.4, 142.2, 122.8, 114.8, 114.2 (t, J

13

= 270.9 Hz), 55.5;

19

F NMR (DMSO-d6) δ –75.99; HRMS (ESI): Calculated for

C9H7F2O4 [M-H]: 217.0312; found: 217.0318. 4.2.6. 2,2-difluoro-2-(4-fluorophenoxy)acetic acid (1f) 1

H NMR (399 MHz, DMSO-d6) δ 7.29 (s, 2H), 7.27 (s, 2H);

19

F NMR (376 MHz,

DMSO-d6) δ -76.30, -115.72 (p, J = 6.5 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.7 (t, J = 39.2 Hz), 160.6 (d, J = 242.9 Hz), 145.3 (d, J = 2.5 Hz), 123.6 (d, J = 8.8 Hz), 116.7 (d, J = 23.5 Hz), 114.3 (t, J = 272.5 Hz); HRMS (ESI): Calculated for C8H4F3O3 [M-H]: 205.0113; found: 205.0111. 14

4.2.7. 2-(4-chlorophenoxy)-2,2-difluoroacetic acid (1g) 1

H NMR (399 MHz, DMSO-d6) δ 7.54 – 7.48 (m, 2H), 7.30 – 7.23 (m, 2H);

(376 MHz, DMSO-d6) δ -76.21;

13

19

F NMR

C NMR (126 MHz, DMSO-d6) δ 160.3 (t, J = 38.9

Hz), 147.9, 130.6, 129.9, 123.1, 114.1 (t, J = 273.1 Hz); HRMS (ESI): Calculated for C8H4ClF2O3 [M-H]: 220.9817; found: 220.9814. 4.2.8. 2–(4–bromophenoxy)–2,2–difluoroacetic acid (1h) Melting point: 53–55 °C; 1H NMR (DMSO-d6) δ 7.65 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H); 13C NMR (DMSO-d6) δ 160.3 (t, J = 38.8 Hz), 148.5, 132.9, 123.4, 118.7, 114.1 (t, J = 272.7 Hz);

19

F NMR (DMSO-d6) δ –76.10; HRMS (ESI): Calculated for

C8H4O3BrF2 [M-H]: 264.9312; found: 264.9310. 4.2.9. 2-(3-bromophenoxy)-2,2-difluoroacetic acid (1i) 1

H NMR (399 MHz, DMSO-d6) δ 7.54 (dtd, J = 8.0, 1.9, 0.9 Hz, 1H), 7.47 – 7.39 (m,

2H), 7.28 (ddq, J = 8.3, 2.2, 1.1 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ -76.13. 13C NMR (100 MHz, DMSO-d6) δ 160.5 (t, J = 38.9 Hz), 150.0 (d, J = 2.5 Hz), 131.7 (d, J = 7.7 Hz), 129.6, 124.3, 122.1, 120.5 (d, J = 4.8 Hz), 114.3 (t, J = 273.3 Hz); HRMS (ESI): Calculated for C8H4BrF2O3 [M-H]: 205.0113; found: 264.9308. 4.2.10. 2,2-difluoro-2-(3-fluorophenoxy)acetic acid (1j) 1

H NMR (399 MHz, DMSO-d6) δ 7.50 (td, J = 8.2, 6.8 Hz, 1H), 7.24 – 7.05 (m, 3H); 19F

NMR (376 MHz, DMSO-d6) δ -76.26 (s, 2F), -110.09 (q, J = 8.5 Hz, 1F); 13C NMR (126 MHz, DMSO-d6) δ 162.2 (d, J = 245.8 Hz), 160.3 (t, J = 38.8 Hz), 150.0 (d, J = 11.1 Hz), 131.3 (d, J = 9.6 Hz), 117.1 (d, J = 3.0 Hz), 114.1 (t, J = 273.9, 273.5 Hz), 113.4 (d, J = 20.9 Hz), 108.9 (d, J = 24.9 Hz); HRMS (ESI): Calculated for C8H4F3O3 [M-H]: 205.0113; found: 205.0112. 4.2.11. 2,2–difluoro–2–(naphthalen–1–yloxy)acetic acid (1k) 1

H NMR (DMSO-d6) δ 8.09 (d, J= 8.1 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.89 (d, J=

8.2 Hz, 1H), 7.67–7.60 (m, 2H), 7.54 (t, J= 8.2 Hz, 1H), 7.4 (d, J= 7.6 Hz, 1H); 13C NMR (DMSO-d6) δ 160.7 (t, J = 39.1 Hz), 144.9, 134.3, 130.0, 127.9, 127.0, 126.3, 125.7, 121.2, 117.0, 114.6 (t, J = 272.8 Hz);

19

F NMR (DMSO-d6) δ –75.60; HRMS (ESI):

Calculated for C12H7O3F2 [M-H]: 237.0363; found: 237.0359. 15

4.2.12. 2–([1,1'–biphenyl]–4–yloxy)–2,2-difluoroacetic acid (1l) 1

H–NMR (DMSO-d6) δ 7.73 (d, J = 7.0 Hz, 2H), 7.66 (d, J = 6.8, 2H), 7.47–7.45 (m, 2H),

7.38–7.36 (m, 1H), 7.32 (d, J = 7.4 Hz, 2H);

13

C NMR (DMSO-d6) δ 161.5 (t, J =

39.2 Hz), 148.7, 139.0, 138.3, 129.0, 128.2, 126.7, 121.5, 114.3 (t, J = 272.2 Hz);

19

F

NMR (DMSO-d6) δ –75.73; HRMS (ESI): Calculated for C14H9O3F2 [M-H]: 263.0520; found: 263.0518. 4.3. Fluorodecarboxylation aryloxydifluoroacetic acids A microwave vial (5 mL) was sealed under an inert atmosphere (Argon glovebox) with

a

stir

bar,

Selectfluor

(177.1 mg,

0.5 mmol,

2 equiv),

silver

trifluoromethanesulfonate (12.8 mg, 0.05 mmol, 20 mol%) and aryloxydifluoroacetic acids (0.25 mmol, 1.0 equiv). To this vial DCM (1.8 mL), trifluoroacetic acid (76.5 μL, 1.0 mmol, 4.0 equiv) and water (0.2 mL) were injected. This mixture was heated for an hour at 55 C. The resulting mixture was cooled down to room temperature, diluted with dichloromethane (4 mL), washed with water (3 X 5 mL), brine (5 mL), dried over anhydrous MgSO4 and filtered. The dried extract was concentrated on a rotary evaporator. The resulting crude product was dissolved in a small quantity of dichloromethane and loaded on to a silica cartridge (10g, Biotage), air dried and eluted with pentane. The pure fractions were combined and the solvent was evaporated to obtain the pure products. 4.3.1. 1-(tert-butyl)-4-(trifluoromethoxy)benzene (2b) Yellow Oil. 1H NMR (399 MHz, Chloroform-d) δ 7.41 – 7.35 (m, 2H), 7.19 – 7.10 (m, 2H), 1.32 (s, 9H); 19F NMR (376 MHz, Chloroform-d) δ -58.4 (s, 3F).6 4.3.2. 1-(tert-butyl)-3-(trifluoromethoxy)benzene (2c) 1

H NMR (399 MHz, DMSO-d6) δ 7.38 – 7.29 (m, 2H), 7.16 (s, 1H), 7.06 – 7.00 (m, 1H),

1.27 (s, 9H); 19F NMR (376 MHz, Chloroform-d) δ -58.21 [19]. 4.3.3. 1-chloro-4-(trifluoromethoxy)benzene (2g) 1

H NMR (399 MHz, Chloroform-d) δ 7.37 (d, J = 9.1 Hz, 2H), 7.18 – 7.13 (m, 2H); 19F

NMR (376 MHz, Chloroform-d) δ -58.67 [20]. 4.3.4. 1-bromo-4-(trifluoromethoxy)benzene (2h) 1

H NMR (399 MHz, Chloroform-d) δ 7.56 – 7.46 (m, 2H), 7.15 – 7.06 (m, 2H); 19F NMR

(376 MHz, Chloroform-d) δ -58.13 [3].

16

4.4. Preparation of arylmercaptodifluoroacetic acids Similar procedure as of ArOCF2CO2H preparation was followed. However, with 5-20 hours of reflux time to obtain the ArSCF2CO2H compounds listed in the Table 4. 4.4.1 2,2-difluoro-2-(phenylthio)acetic acid (3a) 1

H NMR (399 MHz, Chloroform-d) δ 7.65 – 7.60 (m, 2H), 7.51 – 7.45 (m, 1H), 7.43 –

7.37 (m, 2H), 6.05 (s, 1H);

19

F NMR (376 MHz, Chloroform-d) δ -83.8. The data

corroborate with the literature report [21]. 4.4.2. 2-((2,4-dimethylphenyl)thio)-2,2-difluoroacetic acid (3b) 1

H NMR (399 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.31 – 7.22 (m, 2H), 2.40 (s, 3H), 2.29 (s,

3H); 19F NMR (376 MHz, DMSO-d6) δ -80.02; 13C NMR (100 MHz, DMSO-d6) δ 162.5 (t, J = 30.3 Hz), 140.3, 138.3, 136.1, 131.8, 130.7, 123.6, 120.7 (d, J = 284.6 Hz), 20.4, 20.1; HRMS (ESI): Calculated for C10H9O2F2S: 231.0291; found: 231.0284. 4.4.3. 2-((4-chlorophenyl)thio)-2,2-difluoroacetic acid (3c) 1

H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 8.5 Hz, 2H), 7.42 – 7.36 (m, 2H); 19F

NMR (470 MHz, Chloroform-d) δ -83.52; 13C NMR (126 MHz, Chloroform-d) δ 163.1, 138.1, 129.9, 122.9, 119.4 (t, J = 288.9 Hz); HRMS (ESI): Calculated for C8H4O2F2SCl [M-H]: 236.9589; found: 236.9590. 4.4.4. 2-((4-bromophenyl)thio)-2,2-difluoroacetic acid (3d) 1

H NMR (399 MHz, DMSO-d6) δ 7.70 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H); 19F

NMR (376 MHz, DMSO-d6) δ -83.10;

13

C NMR (100 MHz, DMSO-d6) δ 162.2 (d, J =

30.2 Hz), 138.0, 132.6, 124.7, 120.4 (t, J = 288.6 Hz); HRMS (ESI): Calculated for C8H4O2F2SBr: 280.9083; found: 280.9081. 4.4.5. 2-((2-bromophenyl)thio)-2,2-difluoroacetic acid (3e) 1

H NMR (399 MHz, DMSO-d6) δ 7.86 – 7.76 (m, 1H), 7.52 – 7.42 (m, 1H);

19

F NMR

(376 MHz, DMSO-d6) δ -79.81; HRMS (ESI): Calculated for C8H4O2F2SBr: 280.9083; found: 280.9077. 4.4.6. 2-((3-bromophenyl)thio)-2,2-difluoroacetic acid (3f) 17

1

H NMR (399 MHz, DMSO-d6) δ 7.81 – 7.73 (m, 2H), 7.64 (dt, J = 7.8, 1.2 Hz, 1H),

7.45 (t, J = 7.9 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ -79.70; 13C NMR (100 MHz, DMSO-d6) δ 162.1 (t, J = 30 Hz), 137.9, 135.1, 133.6, 131.5, 126.9, 121.9, 120.4 (t, J = 288 Hz); HRMS (ESI): Calculated for C8H4O2F2SBr: 280.9083; found, 280.9083. 4.4.7. 2,2-difluoro-2-((4-methoxyphenyl)thio)acetic acid (3g) 1

H NMR (399 MHz, DMSO-d6) δ 7.52 (d, J = 8.7 Hz, 2H), 7.22 – 6.72 (m, 2H), 3.80

(3H). 19F NMR (376 MHz, DMSO-d6) δ -81.14. 13C NMR (100 MHz, DMSO-d6) δ 162.5 (t, J = 30.5 Hz), 138.2, 120.3 (t, J = 285) 118.5, 115.1, 114.5, 55.4. HRMS (ESI): Calculated for C9H7O3F2S: 233.0084; found: 233.0084. 4.4.8. 2-((3,5-bis(trifluoromethyl)phenyl)thio)-2,2-difluoroacetic acid (3h) 1

H NMR (399 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.25 (s, 3H);

19

F NMR (376 MHz,

DMSO-d6) δ -61.15 (s, 6F), -79.36 (s, 2F); 13C NMR (100 MHz, DMSO-d6) δ 161.9 (t, J = 29.6 Hz), 136.2 (d, J = 4.1 Hz), 131.3 (q, J = 33.5 Hz), 129.0, 124.5 (d, J = 4.0 Hz), 122.7 (q, J = 273.1 Hz), 120.3 (t, J = 288 Hz); HRMS (ESI). Calculated for C10H3O2F8S [M-H]: 338.9726; found: 338.9721. 4.5. Preparation of aryl trifluoromethyl thioethers (ArSCF3) A microwave vial (5 mL) was sealed under inert atmosphere (Ar Glovebox) with a stir bar, Selectfluor (177.1 mg, 0.5 mmol, 2 equiv), silver trifluoromethanesulfonate (12.8 mg, 0.05 mmol, 20 mol%) and arylmercaptodifluoroacetic acids (0.25 mmol, 1.0 equiv). To this vial, DCM (1.8 mL) and trifluoroacetic acid (76.5 μL, 1.0 mmol, 4.0 eq.) as well as water (0.2 mL) were added and the mixture was heated for 90 min at 55 C. The resulting mixture was cooled down to room temperature, diluted with dichloromethane (4 mL), washed with water (3 X 5 mL) and brine (5 mL), dried over anhydrous MgSO4 and filtered. The resulting extract was concentrated in a rotary evaporator. The resulting crude product was dissolved in a small quantity of dichloromethane and loaded on to a silica cartridge (10g, Biotage), air dried and eluted with pentane. The pure fractions were combined and solvent evaporated to obtain the pure products. 4.5.1. (2,4-dimethylphenyl)(trifluoromethyl)sulfane (4b)

18

1

H NMR (399 MHz, Chloroform-d) δ 7.48 (s, 1H), 7.23 – 7.17 (m, 2H), 2.49 (s, 3H),

2.34 (s, 3H);

19

F NMR (376 MHz, Chloroform-d) δ -42.93;

13

C NMR (100 MHz,

Chloroform-d) δ 140.9, 138.8, 136.8, 130.9, 130.0 (q, J = 319.1 Hz), 20.8, 20.8 [22]. 4.5.2. (4-chlorophenyl)(trifluoromethyl)sulfane (4c) 1

H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5, 2H); 19F

NMR (470 MHz, Chloroform-d) δ -43.35. 13C NMR (126 MHz, Chloroform-d) δ 137.7, 137.6, 129.8, 129.3 (q, J = 309.7 Hz); GC-MS m/z (relative intensity): 212 (M) (64), 143 (100), 108 (100), 69 (43) [6]. 4.5.3. (4-bromophenyl)(trifluoromethyl)sulfane (4d) 1

H NMR (400 MHz, Chloroform-d) δ 7.61 – 7.47 (m, 4H); 19F NMR (376 MHz, CDCl3)

δ -43.26; GC-MS m/z (relative intensity) 258 ([M+1]+) (48), 189.1 (40), 108.1 (100), 69 (57). The data corroborate with the literature report [13]. 4.5.4. (2-bromophenyl)(trifluoromethyl)sulfane (4e) 1

H NMR (399 MHz, Chloroform-d) δ 2.59 – 2.54 (m, 1H), 2.54 – 2.49 (m, 1H), 2.20 –

2.08 (m, 2H);

19

F NMR (376 MHz, Chloroform-d) δ -42.52; GC-MS m/z (relative

intensity) 256.1 (M)(100), 187 (48), 108 (94), 69 (61). The data corroborate with the literature report [23]. 4.5.5. (3-bromophenyl)(trifluoromethyl)sulfane (4f) 1

H NMR (399 MHz, Chloroform-d) δ 7.85 – 7.79 (m, 1H), 7.66 – 7.58 (m, 2H), 7.31 (t, J

= 7.9 Hz, 1H);

19

F NMR (376 MHz, Chloroform-d) δ -42.88; GC-MS m/z (relative

intensity) 257.8 (M) (99), 188.7 (78), 107.9 (98.7), 69 (46) [24]. 4.5.6. (4-methoxyphenyl)(trifluoromethyl)sulfane (4g) 1

H NMR (399 MHz, Chloroform-d) δ 7.65 – 7.50 (m, 2H), 7.01 – 6.79 (m, 2H), 3.84 (s,

3H). 19F NMR (376 MHz, Chloroform-d) δ -44.45. GC-MS m/z (relative intensity) 208.4 (7.6), 139 (100), 106.8 (40), 82 (36), 63 (50) [6]. References [1] a) P. Jeschke, M. Schlosser, Chem. Rev. 105 (2005) 827;

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[9] J. C. T. Leung, C. Chatalova-Sazepin, J. G. West, M. Rueda-Becerril, J. F. Paquin, G. M. Sammis, Angew. Chem. Int. Ed. 51 (2012) 10804. [10] J. C. T. Leung, Radical fluorination methods for the synthesis of aryl mono-, di-, and tri- fluoromethyl ethers. Ph.D. Dissertation. University of British Columbia, Vancouver, Canada, 2013. [11] S. Krishnamoorthy, S. D. Schnell, D. Huong, G. K. S. Prakash, Trifluoromethyl ether and trifluoromethyl thioether synthesis by silver catalyzed decarboxylative fluorination. Fluor-21. Presented at the 251st ACS National Meeting (March 13-17, 2016), San Diego, California, USA. [12] Q. Zhang, A. T. Brusoe, V. Mascitti, K.D. Hesp, D. C. Blakemore, J. T. Kohrt, J. F. Hartwig, Angew. Chem Int. Ed. (2016) 9758. [13] M. Zhou, C. Ni, Z. He, J. Hu, Org. Lett. 18 (2016) 3754. [14] C. Chatalova-sazepin, M. Binayeva, M. Epifanov, W. Zhang, P. Foth, C. Amador, M. Jagdeo, B.R. Boswell, G.M. Sammis, Org. Lett. (2016) 4570. [15] L. M. Yagupol'skil, V. A. Korin'ko, Zh. Obshch. Khim. 39 (1969) 1747. [16] Z. Li, Z. Wang, L. Zhu, X. Tan, C. Li, J. Am. Chem. Soc. 136 (2014) 16439. [17] N. R. Patel, R. A. Flowers, J. Org. Chem. 80 (2015) 5834. [18] Y. Han, S. Yang, X. Wang, F. Li, Arch. Pharm. Res. 37 (2014) 440. [19] A. Joshi-pangu, C. Wang, M. R. Biscoe, J. Am. Chem. Soc. 133 (2011) 8478. [20] I. Ben-david, D. Rechavi, E. Mishani, S. Rozen, J. Fluor. Chem. 97 (1999) 75. [21] J. Wu, H. Li, S. Cao, Beilstein J. Org. Chem. 7 (2011) 1070. [22] P. Zhang, M. Li, X.-S. Xue, C. Xu, Q. Zhao, Y. Liu, H. Wang, Y. Guo, L. Lu, Q. Shen, J. Org. Chem. 81 (2016) 7486.

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