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CuI Catalyzed Fluorodesulfurization for the Synthesis of Monofluoromethyl Aryl Ethers Yang Geng, Apeng Liang, Xianying Gao, Chengshan Niu, Jingya Li, Dapeng Zou, Yusheng Wu, and Yangjie Wu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01438 • Publication Date (Web): 13 Jul 2017 Downloaded from http://pubs.acs.org on July 14, 2017

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The Journal of Organic Chemistry

CuI Catalyzed Fluorodesulfurization for the Synthesis of Monofluoromethyl Aryl Ethers Yang Geng,† Apeng Liang,† Xianying Gao,† Chengshan Niu,‡ Jingya Li,‡ Dapeng Zou,*,† Yusheng Wu,*,‡,§ and Yangjie Wu,* ,† †

The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450052, People’s Republic of China ‡

Tetranov Biopharm, LLC. and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450052, People’s Republic of China §

Tetranov International, Inc. 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA.

Supporting Information Placeholder Ar

O

O S

CuI, DAST CH2Cl2, rt, 18 h

Ar

O

1) broad substrates scope F 2) good functional group tolerance 3) suitable for deuterated compounds up to 28 examples and 99% yield

ABSTRACT: An efficient CuI catalyzed fluorodesulfurization for the synthesis of monofluoromethyl aryl ethers using DAST at room temperature has been developed. This approach exhibits a good functional group tolerance, a broad substrates scope and high synthesis efficiency.

■ INTRODUCTION Fluoromethyl aryl ethers are of significant importance for the 1 materials, agricultural and pharmaceutical industries. For examples, the monofluoromethyl aryl ethers play a conspicuous and increasingly important role in medical imaging filed, which are widely used as PET (Positron Emission Tomography) and SPECT (Single-Photon Emission Computed Tomog2 raphy) radiotracers. For half a century, various methods to form monofluoro-, difluoro- and trifluoromethyl ethers have 3, 4 been developed. Among them, most of the reported synthesis strategies for monofluoromethyl aryl ethers usually use the following methods (Scheme 1). (1) Direct monofluoromethylation of alkoxides with monofluoromethylation 5 6 7 reagents such as FCH2Cl, FCH2Br, FCH2I and 8 PhSO(NTs)CH2F. (2) Halogen exchange reaction using KF 9 and TBAF as fluoride sources. (3) Oxidative fluorination of 10 and pbenzylic alcohols with XeF2 11 trifluoromethylphenyl(difluoro)-λ-3-bromane. (4) Fluorode12 13 carboxylation of alkoxyacetic acids using XeF2, NFSI and 14, 15 selectfluor as fluoride reagents. (5) Fluorodesulfurization, 16 17 for examples, XeF2 and IF5-pyridine-HF were used in the fluorodesulfurization reaction. Among these methods, fluorodesulfurization has more advantages due to its easily obtained substrates, inexpensive fluorinated reagents and mild reaction conditions. Using commercially available DAST for the synthesis of monofluoromethyl aryl ethers under mild conditions was 9b firstly reported by Benneche and co-workers in 1999. However, this method needs long reaction time and only three substrates were reported. Particularly, the sulphoxide derivatives are prepared from methylthiomethyl ethers via an oxi-

dation reaction using peroxide. In addition, when using this method to synthesize other monofluoromethyl aryl ethers in our new drug development research, the reaction yields were not satisfactory.

Scheme 1. Methods for the Synthesis of Monofluoromethyl Aryl Ethers. Previous work R

OH X

R

O fluoromethylation (1)

O

halogen-F-exchange

fluorodecarboxylation R (4) R

O

(2) OH R

oxidative fluorination

O

OH S

F

R

O

R

O

fluorodesulfurization (5)

O S

(3)

This work Ar OH

Ar

O

O S

CuI, DAST CH2Cl2, rt

Ar

O

F

Metal containing Lewis acids are sometimes used as catalysts 18 for the fluorination reaction. For instances, ZnI2 was used together with DAST to synthesize α-fluoro thioethers, and SbCl3 was introduced to promote the fluorodesulfurization 19 for the preparation of trifluoromethyl aryl ethers. Therefore, we tried to introduce metal containing Lewis acids to the Benneche’s fluorodesulfurization system. Herein, an efficient CuI catalyzed fluorodesulfurization for the synthesis of monofluoromethyl aryl ethers using DAST as fluoride sources was reported. ■ RESULTS AND DISCUSSION Table 1. Screening Reaction Conditions

ACS Paragon Plus Environment

a


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

O

O S

O

DAST (2.0 equiv), catalyst (x mol %)

F

O

S

F

+

CH2Cl2, rt, time 1a

2a

Scheme 2. CuI Catalyzed Fluorodesulfurization for the Synthesis of Monofluoromethyl Aryl Ethers.a,b, c

3a Ar

entry

catalyst

x

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b

time (h)

yield(%) 3a

O

2a A: 99%; B: 28%b

---

---

18 36

28 65

55 25

3 4

AlCl3 SnCl2

10 10

18 18

80 58

n. d n. d

5 6

ZnI2 ZnCl2

10 10

18 18

94 85

trace trace

7 8

CuCl CuI

10 10

18 18

90 96

trace trace

9 10

Cu2O Cu(OAc)2

10 10

18 18

20 10

36 68

11 12

Cu(NO3)2 Pd(OAc)2

10 10

18 18

8 25

60 59

1 5

18 18

90 93

15 16

CuI CuI

20 30

18 12

99/99 94

O

F

F O

F

O

F

c

2b A: 95%; B: 24%b

O

2c A: 99%; B: 29%b

O

F

F

NC O

2e A: 65%b; B: 12%b

Br

O

O

2i A: 95% , 67%; B: 34%b

O Br

b

O

O O

F

2h A: 98%b, 80%; B: 40%b Ph

F

F

O

2k A: 60%b; B: 16%b

F

O

F

2l A: 99%; B: 41%b O

F

F

O O 2n A: 91%b, 82%; B: 40%b

2m A: 95%; B: 38%b O

F

O Br

F

2j A: 80% , 36%; B: 21%b

b

F

2gd A: 95%b B: 38%b; 88%b (36 h)

2f A: 90%; B: 25%b

Br

F

O

2d A: 89%; B: 28%b

Cl

F

F

COOEt

Br

F

O

NO2

trace trace c

Ar

2a-2y O

1 2

CuI CuI

Method A: 20 mol% CuI, 2.0 eq.DAST Method B: 2.0 eq.DAST

1a-1y

2a

13 14

O S

O

OHC

2o A: 60%b; B: 12%b O F

2p A: 75%b, 60% (48 h) B: 15%b (48 h) O F

F N Bz

S

2q A: 40%b, 48 h B: 0%b, 48 h

NO2

O

2r A: 92%; B: 29%b

N

2s A: 90%; B: 28%b

2t A: 0%b; B: 0%b O

n.d. n.d.

O O

17 CuI 50 8 90 n.d. Reaction conditions: 1a (0.5 mmol), DAST (1.0 mmol), 2.5 b 19 mL of CH2Cl2, 25 °C. Yields were determined by F NMR spectroscopy with 2-(4-(trifluoromethyl)phenyl) acetonitrile c as a standard. Isolated yield. n.d. = no detected.

F F

2u A: 99%; B: 23%b

O

Br O

F

2v A: 99%; B: 52%b

F O

2w A: 99%b; B:48%b

F

O

O NHBz 2x A: 90%; B: 35%b

a

F

H

H

O 2y A: 92%; B: 40%b

a

Firstly, compound 1a (prepared from naphthalen-2-ol and 20 chloro(methylsulfinyl)methane ) (see Experimental Section) was treated with DAST (2.0 equiv) at room temperature for 18 hours, 55% yield of 3a was detected, with only 28% yield of the desired product 2a (Table 1, entry 1) which was 19 determined by F NMR spectroscopy. The compound 3a is analogous to the side product reported by the group of 16 Benneche in 1996. The mechanism of this side reaction is 18, 21 Prolonging the similar to the Pummerer rearrangement. reaction time to 36 hours, the yield of 2a was increased to 65% (entry 2) accompanied with 25% yield of 3a. Then, various Lewis acids were screened and most of them (entries 3-8) were found to play a positive role in the fluorodesulfurization reaction. In particular, in the presence of ZnI2 (entry 5) and CuI (entry 8), the reaction gave the desired product 2a with 94% and 96% yields respectively. So CuI was selected as the optimal catalyst. Furthermore, the amount of catalyst was also studied. Reducing the catalyst loading to 1 mol % and 5 mol % (entries 13 and 14), the yields of 2a was dropped to 90% and 93%. To our delight, when the amount of CuI was adjusted to 20 mol %, the desired product 2a was obtained in 99% yield, and the byproduct 3a was not detected (entry 15). More than 30 mol % of CuI (entries 16 and 17) was not conducive to the reaction. Thus, the optimum reaction conditions were determined as the combination of 1.0 equiv of 1a, 20 mol % of CuI, 2.0 equiv DAST, in DCM at room temperature for 18 hours.

Standard reaction conditions: method A: 1 (0.5 mmol), CuI (20 mol %), DAST (1.0 mmol) in 2.5 mL of CH2Cl2 at 25 °C for 18 h; Method B: 1 (0.5 mmol), DAST (1.0 mmol) in 2.5 ml of CH2Cl2 at 25 °C for 18 h;(as to the substrates 1s, the amount of b 19 DAST was 2.0 mmol). Yields were determined by F NMR spectroscopy with 2-(4-(trifluoromethyl)phenyl) acetonitrile c d as standard. Isolated yield. Compound 2g was one of the products reported in Benneche’s work. With the optimal reaction conditions in hand, the substrate scope was investigated as shown in Scheme 2. As a contrast, the method without catalyst CuI was also applied to the same substrates. Various substrates containing aromatic rings such as benzene, naphthalene, benzothiophene, binaphthalene and indoline were tested. Functional groups including halide, ester, acetyl, benzoyl, phenyl, cyano, alkyl, nitro and aryl, were compatible under the standard conditions. The reaction proceeded smoothly to give the monofluoromethyl naphthyl ethers in moderate to good yields. When using the methylsulfinylmethyl ethers substituted at the α and β position of naphthalene, the fluorodesulfurization reactions afforded the desired products (2a and 2b) in 99% and 95% isolated yields, respectively. Substrates containing naphthalene with electron-withdrawing groups were also transformed into monofluoromethoxy compounds (2c, 2d, 2f) in high yields. The fluorodesulfurization reaction occurred on the substrates with benzene rings and gave the various monofluoromethyl phenyl ethers 2g-2q in 40-99%

2


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yields. Substrates containing ketones and aldehydes are sensitive to DAST, but the reaction were also found to give 2e 19 and 2o in 65% and 60% yields detected by F NMR spectroscopy, respectively. The structures of crude 2e and 2o were 1 19 confirmed by H NMR, F NMR and GC-MS. The method used for sulfur or nitrogen containing substrates gave the desired products 2r and 2s in 92% and 90% isolated yields, respectively. Unfortunately, the product 2t was not detected when substrate containing pyridine unit was treated by this method. Introduction of bis-OCH2F groups into one molecule was also successful by using 4.0 eq. DAST and the desired product 2u was obtained in 99% yield. Monofluoromethyl benzyl ether such as 2v and 2w were obtained in 99% yield, which were sensitive to the moisture. We further applied this method to more complex organic molecules. For examples, under the standard conditions, monofluoromethoxy group containing compounds 2x and 2y were obtained in 90% and 92% yields. Among them, 2x is an intermediate of 2a potential PET tracer for imaging amino acid transport, and compound 2y contains a steroid ring would be a potential 2b antiproliferative agent. The contrast experiments between the two methods shows that the fluorodesulfurization without CuI has low efficiency for most of the substrates. Particularly, the nitro group containing substrates only gave the desired products 2p and 2q in 15% and 0% yields. While, in case of the CuI catalyzed fluorodesulfurization, the desired product 2p and 2q was obtained in 75% and 40% yields, respectively. Scheme 3. Application for Preparing Deuterated Monoa,b,c fluoromethyl Aryl Ethers.

Ar

O

D

O D S D

D

20 mol% CuI, 2.0 eq DAST

Ar

D

O

D

F

Scheme .4. Scalability of the Fluorodesulfurization of 1c O 0.2 equiv CuI, 2.0 equiv DAST O

O S

CH2Cl2, rt,18 h

Br

Br

2c 2.54 g (9.96mol) O

1c 3.00 g (10 mmol)

F

99%

F

2.0 equiv DAST CH2Cl2, rt,18 h

28%

Br 2c 0.72 g (2.82 mmol)

The CuI catalyzed fluorodesulfurization method is also suitable for the application in grams scale experiment (Scheme 4). Under the standard reaction conditions, 2.54 g of compound 2c was obtained in 99% yield from 3.00 g of 1c. For a comparison, the fluorodesulfurization without catalyst provided 0.72 g of product 2c in 28% yield. ■CONCLUSION In summary, the introduction of CuI to an old fluorodesulfurization system improves the reaction process, provides an efficient approach for the synthesis of monofluoromethyl aryl ethers. This method exhibits a good functional group tolerance and a broad substrates scope. Monofluoromethyl aryl ethers with different aromatic rings and various substituted groups were synthesized under mild conditions. The concise approach is also suitable for preparation of deuterated monofluoromethyl aryl ethers and for the larger scale application. ■EXPERIMENTAL SECTION

D

1z-1ab

2z-2ab

O D 2z 99%, 99.5 atom%D

F

O

D Br

D

F D

2ab 80%, 99.5 atom%D

F D

D O

H

H

2ac 92%, 99.5 atom%D

a

Standard reaction conditions: 1 (0.5 mmol), CuI (20 mol %), b DAST (1.0 mmol) in 2.5 mL of CH2Cl2 at 25 °C for 18 h. Ic 1 solated yield. Deuterium content was determined by H NMR spectroscopy. Introduction of deuterium into organic pharmaceutical molecules offers potential benefits, such as improving exposure 22 profiles and decreasing production of toxic metabolites. The approaches of introducing OCD2F group into organic molecules were rarely reported. To date, only two methods 2c 2d were reported using CD2I2 and CD2BrF as deuterium sources. Our protocol was attempted to prepare deuterated monofluoromethyl aryl ethers. Reactions occurred on deuterated substrates (Scheme 3, 1z, 1ab, 1ac) to afford the products (2z, 2ab, 2ac) in 99%, 80%, and 92% isolated yields, respectively. Remarkably, the deuterium substitution rates (with 99.5 atom% D) were not changed under the reaction conditions which were consistent with the substrates.

All manipulations were carried out in glass reaction tube equipped with a magnetic stir bar under argon atmosphere. Unless otherwise mentioned, solvents and reagents were purchased from commercial sources and used as received. Analytical thin-layer chromatography was performed using glass plates pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin layer chromatography plates were visualized by exposure to ultraviolet light. Melting points were recorded by XT4A micro Melting point Measurement Instruments, thermometer was unrevised. The transformation progress and Mass spectra were indicated by LC-MSD-Trap-XCT instrument or GCMS (Thermo Fisher Scientific DSQ II). The high resolution mass spectrum were received via Agilent Technologies 6540 UHD Accurate-mass Q-TOF LC/MS, with ESI as ion source and Thermo Scientific Q Exactive GC Orbitrap GC-MS. Moreover, NMR spectra were obtained on Bruker AVANCE III 400 systems using CDCl3 or DMSO-d6 as solvent, TMS as internal standard substance, with proton, fluorine and carbon resonances at 400, 376 and 100 MHz, respectively. 20

Sodium hydride (480 mg, 12 mmol, 60% in mineral oil) was added to a solution of phenol (10 mmol) (or benzyl alcohol) in dry DMF (10 mL) at 0 oC under argon atmosphere.

General procedure for the synthesis of substrates

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After 30 min, potassium iodide (1.99 g, 12 mmol), chloro(methylsulfinyl)methane (1.35 g, 12 mmol) was added. Then, the reaction mixture was stirred at 80 °C for 36 h and monitored by TLC. When the reaction finished, the mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo, and the resulting residue was purified by flash column chromatograph to give the pure products. The products were characterized by 1H NMR, 13C NMR, HRMS and LC-MS. 2-((Methylsulfinyl)methoxy)naphthalene23 (1a, 1.76 g, yield 80%): white solid; mp 103-104 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.79-7.74 (m, 3H), 7.48-7.45 (m, 1H), 7.40-7.37 (m, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.21 (dd, J = 8.9 Hz, 2.6 Hz, 1H), 5.13 (d, J = 10.1 Hz, 1H), 4.95 (d, J = 10.1 Hz, 1H), 2.70 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 155.3, 134.1, 130.1, 129.9, 127.7, 127.1, 126.9, 124.8, 118.1, 109.0, 84.1, 35.9. HRMS (ESI-TOF) m/z: Calcd for C12H13O2S [M+H]+: 221.0636; Found: 221.0634. LC-MS (ESI, m/z): [M+H]+ 221.1. 1-((Methylsulfinyl)methoxy)naphthalene23 (1b, 1.72 g, yield 78%): white solid; mp 55-56 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 8.22-8.20 (m, 1H), 7.84-7.81 (m, 1H), 7.56-7.51 (m, 3H), 7.40 (t, J = 7.9 Hz 1H), 7.05 (d, J = 7.6 Hz, 1H), 5.25 (d, J =10.0 Hz, 1H), 5.04 (d, J = 10.0 Hz, 1H), 2.75 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 153.1, 134.6, 127.7, 126.9, 126.0, 125.5, 125.3, 122.8, 121.5, 106.9, 84.4, 36.1. HRMS (ESI-TOF) m/z: Calcd for C12H13O2S [M+H]+ : 221.0636; Found: 221.0634. LC-MS (ESI, m/z): [M+H]+ 221.1. 2-((Methylsulfinyl)methoxy)-6bromonaphthalene23 (1c, 2.53 g, yield 85%): white solid; mp 105-106 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.94 (d, J = 1.4 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 8.7 Hz, 1.9 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.25 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 5.12 (d, J = 10.2 Hz, 1H), 4.99 (d, J = 10.2 Hz, 1H), 2.73 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 155.6, 132.6, 130.9, 130.2, 129.7, 129.2, 128.7, 119.2, 118.4, 109.1, 84.1, 35.8. HRMS (ESI-TOF) m/z: Calcd for C12H12BrO2S [M+H]+: 298.9741; Found: 298.9739. LC-MS (ESI, m/z): [M+H]+ 299.0, 301.0. Ethyl 3-(methylsulfinylmethoxy)-2-naphthoate23 (1d, 2.36 g, yield 75%): white solid; mp 63-64 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 8.36 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.48-7.44 (m, 2H), 5.23 (d, J = 9.4 Hz, 1H), 5.00 (d, J = 9.4 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.82 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 165.4, 153.5, 135.6, 133.3, 128.9, 128.8, 128.7, 126.9, 125.7, 122.0, 111.4, 84.7, 61.3, 36.1, 14.4. HRMS (ESI-TOF) m/z: Calcd for C15H16O4SNa [M+Na]+: 315.0667; Found: 315.0665. LC-MS (ESI, m/z): [M+ Na ]+ 315.1. 6-((Methylsulfinyl)methoxy)naphthalene-2carbonitrile23 (1f, 1.72 g, yield 70%):brown solid; mp 135136 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 8.16 (s, 1H), 7.84 (t, J = 8.9 Hz, 2H), 7.60 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.9 Hz, 2.5 Hz, 1H),

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5.16 (d, J = 10.3 Hz, 1H), 5.08 (d, J = 10.3 Hz, 1H), 2.76 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 157.6, 135.9, 133.8, 130.6, 128.6, 128.3, 127.5, 120.1, 119.2, 109.0, 108.1, 83.8, 35.7. HRMS (ESI-TOF) m/z: Calcd for C13H12NO2S [M+H]+: 246.0589; Found: 246.0587. LC-MS (ESI, m/z): [M+H]+ 246.1. 1-((methylsulfinyl)methoxy)-4-chlorobenzene (1g, 1.75 g, yield 78%):yellow solid; mp 65-67 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.28-7.26 (m, 2H), 7.00-6.99 (m, 2H), 4.97 (d, J = 10.3 Hz, 1H), 4.90 (d, J = 10.3 Hz, 1H), 2.68 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 156.2, 129.7, 128.0, 117.0, 84.5, 35.4. LC-MS (ESI, m/z): [M+H]+ 205.1, [M+Na]+ 227.0. The spectral data are consistent with those previously reported in the literature.9b 1-((Methylsulfinyl)methoxy)-4-bromobenzene. (1h, 1.98 g, yield 80%): white solid; mp 71-72 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.45-7.41 (m, 2H), 6.97-6.93 (m, 2H), 4.97 (d, J = 10.3 Hz, 1H), 4.88 (d, J = 10.3 Hz, 1H), 2.67 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 156.7, 132.7, 117.5, 115.5, 84.4, 35.6. LC-MS (ESI, m/z): [M+H]+ 249.1, 250.9. The spectral data are consistent with those previously reported in the literature.24 1-((Methylsulfinyl)methoxy)-3-bromobenzene23 (1i, 1.86 g, yield 75%): yellow solid; mp 58-60 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.22-7.19 (m, 3H), 7.02-7.00 (m, 1H), 4.99 (d, J = 9.8 Hz, 1H), 4.89 (d, J = 9.8 Hz, 1H), 2.69 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 158.1, 130.9, 126.2, 123.0, 119.2, 114.3, 84.1, 35.6. HRMS (ESI-TOF) m/z: Calcd for C8H10BrO2S [M+H]+: 248.9585, 250.9564; Found: 248.9582, 250.9562. LC-MS (ESI, m/z): [M+H]+ 249.0, 250.9. 1-((Methylsulfinyl)methoxy)-2-bromobenzene23 (1j, 1.49 g, yield 60%): yellow solid; mp 54-55 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.56 (dd, J = 7.9 Hz, 1.6 Hz, 1H), 7.32-7.28 (m, 1H), 7.17 (dd, J = 8.3 Hz, 1.4 Hz, 1H), 6.996.94 (m, 1H), 5.07 (d, J = 10.1 Hz, 1H), 4.93 (d, J = 10.1 Hz, 1H), 2.77 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 154.1, 133.7, 128.9, 124.5, 115.9, 112.8, 84.7, 36.0. HRMS (ESITOF) m/z: Calcd for C8H10BrO2S [M+H]+: 248.9585, 250.9564; Found: 248.9582, 250.9559. LC-MS (ESI, m/z): [M+H]+ 249.0, 250.9. 1-((Methylsulfinyl)methoxy)-4-phenylbenzene23 (1l, 2.10 g, yield 85%): white solid; mp 109-110 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.57-7.53 (m, 4H), 7.44-7.41 (m, 2H), 7.35-7.31 (m, 1H), 7.14-7.10 (m, 2H), 5.07 (d, J = 10.2 Hz, 1H), 4.91 (d, J = 10.2 Hz, 1H). 2.71 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 157.0, 140.3, 136.2, 128.9, 128.5, 127.1, 126.9, 115.9, 84.3, 35.8. HRMS (ESI-TOF) m/z: Calcd for C14H15O2S [M+H]+: 247.0793; Found: 247.0790. LC-MS (ESI, m/z): [M+H]+ 247.1. 1-((Methylsulfinyl)methoxy)-3-(4methoxyphenyl)benzene23 (1m, 2.32 g, yield 84%): white solid; mp 99-101 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.51 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H), 7.27-7.22 (m, 2H), 6.98 (d, J = 8.6 Hz, 3H), 5.09 (d, J = 10.1 Hz, 1H), 4.91 (d, J = 10.1 Hz, 1H), 3.85 (s, 3H), 2.71 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 159.5, 157.8, 142.9, 132.8, 130.1, 128.2,

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121.5, 114.3, 114.0, 113.5, 84.3, 55.4, 35.8. HRMS (ESI-TOF) m/z: Calcd for C15H17O3S [M+H]+: 277.0898; Found: 277.0897. LC-MS (ESI, m/z): [M+H]+ 277.1. Methyl 4-((methylsulfinyl)methoxy)benzoate23 (1n, 1.64 g, yield 72%): white solid; mp 74-75 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 8.04-8.01 (m, 2H), 7.10-7.06 ( m, 2H), 5.07 (d, J = 10.2 Hz, 1H), 4.97 (d, J = 10.2 Hz, 1H), 3.90 (s, 3H), 2.72 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 166.4, 160.9, 131.8, 124.9, 115.1, 83.6, 52.1, 35.7. HRMS (ESITOF) m/z: Calcd for C10H13O4S [M+H]+: 229.0535; Found: 229.0533. LC-MS (ESI, m/z): [M+H]+ 229.1. 1-((Methylsulfinyl)methoxy)-4-nitrobenzene23 (1p, 1.40 g, yield 65%): yellow solid; mp 129-130 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 8.25-8.21 (m, 2H), 7.28-7.17 (m, 2H), 5.06 (d, J = 10.5 Hz, 2H), 2.74 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 162.2, 143.1, 126.0, 115.7, 83.8, 35.4. HRMS (ESI-TOF) m/z: Calcd for C8H10NO4S [M+H]+: 216.0331; Found: 216.0327. LC-MS (ESI, m/z): [M+H]+ 216.1. 5-((Methylsulfinyl)methoxy)benzo[b]thiophene23 (1r, 1.81 g, yield 80%): white solid; mp 79-79 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.76 (d, J = 8.8 Hz, 1H), 7.487.46 (m, 2H), 7.27 (d, J = 5.2 Hz, 1H), 7.08 (dd, J = 8.8 Hz, 2.5 Hz, 1H), 5.07 (d, J = 10.2 Hz, 1H), 4.93 (d, J = 10.2 Hz, 1H). 2.69 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 155.3, 140.6, 134.4, 128.5, 123.7, 123.6, 114.9, 108.7, 85.0, 35.6. HRMS (ESI-TOF) m/z: Calcd for C10H11O2S2 [M+H]+: 227.0200; Found: 227.0198. LC-MS (ESI, m/z): [M+H]+ 227.1; [M+Na]+ 249.1. (4-((Methylsulfinyl)methoxy)indolin-1yl)(phenyl)methanone (1s, 2.46 g, yield 78%): yellow solid; mp 118-120 °C; 1H NMR (400 MHz, DMSO-d6, ppm): δ = 7.58-7.47 (m, 6H), 7.16 (brs, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.29 (d, J = 10.7 Hz, 1H), 5.10 (d, J = 10.7 Hz, 1H). 4.03 (t, J = 8.2 Hz, 2H), 3.03 (t, J = 8.3 Hz, 2H), 2.62 (s, 3H). 13C NMR (100 MHz, DMSO-d6, ppm): δ = 168.1, 153.8, 144.2, 137.0, 130.1, 128.5, 126.8, 120.5, 110.9, 109.1, 84.6, 50.6, 34.2, 24.8. HRMS (ESI-TOF) m/z: Calcd for C17H18NO3S [M+H]+: 316.1007; Found: 316.1007. LC-MS (ESI, m/z): [M+H]+ 316.1. 1-(((Methylsulfinyl)methoxy)methyl)-2bromobenzene23 (1v, 1.71 g, yield 65%): yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.57 (dd, J = 8.0 Hz, 1.0 Hz, 1H), 7.47 (dd, J = 7.6 Hz, 1.5 Hz, 1H), 7.36-7.32 (m, 1H), 7.22-7.18 (m, 1H), 4.92 (q, J = 12.3 Hz, 2H), 4.56 (s, 2H), 2.62 (s, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ = 135.7, 132.9, 130.0, 129.9, 127.6, 123.3, 87.1, 74.8, 35.4. HRMS (ESITOF) m/z: Calcd for C9H11BrO2SNa [M+Na]+: 284.9561, 286.9540; Found: 284.9562, 286.9543. LC-MS (ESI, m/z): [M+H]+ 263.0, 265.0. General procedure for the synthesis of deuterated substrates Sodium hydride (480 mg, 12 mmol, 60% in mineral oil) was added to a solution of phenol (10 mmol) in dry DMF (10 mL) at 0 °C under argon atmosphere. After 30 min, potassium iodide (1.99 g, 12 mmol), d5chloro(methylsulfinyl)methane (1.40 g, 12 mmol) was added, then the reaction mixture was stirred at 80 °C for 36 h. After the reaction finished, the mixture was diluted with ethyl acetate, and then washed with brine, dried over an-

hydrous Na2SO4, concentrated, and purified by flash column chromatograph. The atom% D of the product was lower than 90% under the reaction condition. The crude product was dissolved in 1, 4-dioxane, added with 3.0 eq. K2CO3 and 50 eq. D2O, heated to 100 °C for 20 h. The reaction mixture was cooled to room temperature and extracted with CH2Cl2. The CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to get the pure product. The products were characterized by 1 H NMR, 13C NMR, HRMS and LC-MS. The atom% D was determined by 1H NMR. 2-((d5-Methylsulfinyl)methoxy)naphthalene23 (1z, 1.80 g, yield 80%): white solid; mp 105-106 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.81-7.76 (m, 3H), 7.507.46 (m, 1H), 7.42-7.33 (m, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 9.0 Hz, 2.6 Hz, 1H). 13C NMR (100 MHz, CDCl3, ppm): δ = 155.2, 134.1, 130.1, 129.9, 127.7, 127.1, 126.9, 124.8, 118.1, 109.0, 84.1 (m), 35.9 (m). HRMS (ESITOF) m/z: Calcd for C12H8D5O2S [M+H]+: 226.0950; Found: 226.0946. LC-MS (ESI, m/z): [M+H]+ 226.1. 1-((d5-Methylsulfinyl)methoxy)-4bromobenzene23 (1ab, 2.02 g, yield 80%): white solid; mp 72-73 °C; 1H NMR (400 MHz, CDCl3, ppm): δ = 7.43 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H). 13C NMR (100 MHz, CDCl3, ppm): δ = 156.6, 132.7, 117.5, 115.5, 84.4 (m), 35.6 (m). HRMS (ESI-TOF): Calcd for C8H5D5BrO2S [M+H]+: 253.9899, 255.9878; Found: 253.9896, 255.9877. LC-MS (ESI, m/z): [M+H]+ 254.0, 256.0. General procedure for the synthesis of (deuterated) monofluoromethyl aryl ethers. A dried glass reaction tube equipped with a magnetic stir bar was charged with 1 (0.5 mmol), CuI (19 mg, 0.1 mmol) and CH2Cl2 (2.5 mL), then DAST (0.13 ml, 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction progress was monitored by TLC. After the reaction finished, the reaction mixture was added with saturated NaHCO3 solution, and extracted with CH2Cl2 (5 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated, and the residue was purified by flash column chromatograph to give the pure product. The products were characterized by 1H NMR, 13C NMR, 19F NMR, HRMS and GC-MS. 2-(Fluoromethoxy)naphthalene (2a, 87.0 mg, yield 99%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.79-7.75 (m, 3H), 7.45-7.37 (m, 3H), 7.25-7.21 (m, 1H), 5.80 (d, J = 54.6 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -148.8 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 154.6 (d, J = 3.0 Hz), 134.2, 130.2, 129.8, 127.7, 127.3, 126.7, 124.8, 118.5 (d, J = 1.1 Hz), 111.1 (d, J = 1.0 Hz), 100.9 (d, J = 217.3 Hz). GC-MS (EI, m/z): [M]+ 175.8. The spectral data are consistent with those previously reported in the literature.5 1-(Fluoromethoxy)naphthalene (2b, 83.6 mg, yield 95%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 8.22-8.20 (m, 1H), 7.81-7.79 (m, 1H), 7.56 (d, J = 8.3

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Hz, 1H), 7.50-7.47 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.87 (d, J = 51.4 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -148.2 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 152.8 (d, J = 3.3 Hz), 134.6, 127.7, 126.7, 126.0, 125.8 (d, J = 1.1 Hz), 125.7, 123.3, 121.8, 109.2 (d, J = 1.1 Hz), 101.1 (d, J = 217.7 Hz). GC-MS (EI, m/z): [M]+ 176.1. The spectral data are consistent with those previously reported in the literature.5 2-Bromo-6-(fluoromethoxy)naphthalene25 (2c, 125.7 mg, yield 99%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.96 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 5.82 (d, J = 54.4 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -149.3 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 154.8 (d, J = 2.9 Hz), 132.6, 131.2, 130.0, 129.7, 128.9, 119.6, 118.5, 111.1, 100.7 (d, J = 218.0 Hz). HRMS (EI-Orbitrap) m/z: Calcd for C11H8BrFO [M]+ ： 253.97426, 255.97221; Found: 253.97380, 255.97173. GCMS (EI, m/z): [M]+ 254.0, 256.0 Ethyl 3-(fluoromethoxy)naphthalene-2carboxylate23 (2d, 110.3 mg, yield 89%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 8.35 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.58-7.53 (m, 2H), 7.47-7.43 (m, 1H), 5.84 (d, J = 54.6 Hz, 2H), 4.43 (q, J = 7.16 Hz, 2H), 1.42 (t, J =7.2 Hz, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ = -149.0 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 165.7, 152.6 (d, J = 2.9 Hz), 135.6, 132.8, 129.3, 128.7, 128.6, 127.1, 125.8, 122.6 (d, J = 1.3 Hz), 114.3, 101.9 (d, J = 218.3 Hz), 61.3, 14.3. HRMS (ESI-TOF) m/z: Calcd for C14H13FO3Na [M+Na]+: 271.0746; Found: 271.0744. 6-(Fluoromethoxy)naphthalene-2-carbonitrile23 (2f, 111.7 mg, yield 90%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 8.19 (s, 1H), 7.85 (t, J = 9.3 Hz, 2H), 7.61 (dd, J = 8.5 Hz, 1.6 Hz, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.36 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 5.84 (d, J = 54.6 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -150.4 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 156.7 (d, J = 2.9 Hz), 135.9, 133.8, 130.4, 128.9, 128.5, 127.3, 120.4, 119.2, 110.7 (d, J = 1.3 Hz), 108.2, 100.2 (d, J = 219.3 Hz). HRMS (ESI-TOF) m/z: Calcd for C12H8FNONa [M+Na]+: 224.0488; Found: 224.0484. 1-Bromo-4-(fluoromethoxy)benzene. (2h, 81.6 mg, yield 80%): yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.45-7.41 (m, 2H), 6.98-6.94 (m, 2H), 5.67 (d, J = 54.4 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = 149.1 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 155.9 (d, J = 3.0 Hz), 132.6, 118.5 (d, J = 1.0 Hz), 116.1, 100.7 (d, J = 218.2 Hz). GC-MS (EI, m/z): [M]+ 203.6, 205.8. The spectral data are consistent with those previously reported in the literature.11a 1-bromo-3-(fluoromethoxy)benzene. (2i, 68.3 mg, yield 67%): yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.18-7.10 (m, 3H), 6.96-6.93 (m, 1H), 5.61 (d, J = 54.4 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -149.2 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 157.4 (d, J =

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3.1 Hz), 130.8, 126.7, 122.8, 120.1 (d, J =1.4 Hz), 115.4 (d, J = 1.3 Hz), 100.5 (d, J = 218.8 Hz). GC-MS (EI, m/z): [M]+ 203.6, 205.8. The spectral data are consistent with those previously reported in the literature.14b 1-Bromo-2-(fluoromethoxy)benzene23 (2j, 36.7 mg, yield 36%): yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.57 (dd, J = 7.9 Hz, 1.5 Hz, 1H), 7.31-7.27 (m, 1H), 7.19-7.16 (m, 1H), 7.01-6.97 (m, 1H), 5.74 (d, J = 50.0 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -149.3 (s).13C NMR (100 MHz, CDCl3, ppm): δ = 153.5 (d, J = 3.0 Hz), 133.7, 128.8, 124.9, 117.3, 113.2 (d, J = 1.8 Hz), 101.1 (d, J = 219.6 Hz). HRMS (EI-Orbitrap) m/z: Calcd for C7H6BrFO [M]+ ： 203.95861, 205.95656; Found: 203.95805, 205.95574. GC-MS (EI, m/z): [M]+ 203.6, 205.8. 1-Phenyl-4-(fluoromethoxy)benzene (2l, 100.0 mg, yield 99%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.55-7.52 (m, 4H), 7.42-7.39 (m, 2H), 7.337.29 (m, 1H), 7.14-7.11 (m, 2H), 5.72 (d, J = 54.6 Hz, 2H). 19 F NMR (376 MHz, CDCl3, ppm): δ = -148.4 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 156.3 (d, J = 3.2 Hz), 140.5, 136.7, 128.8, 128.4, 127.2, 127.0, 117.0 (d, J = 1.0 Hz), 100.8 (d, J = 217.4 Hz). GC-MS (EI, m/z): [M]+ 202.0. The spectral data are consistent with those previously reported in the literature.5 1-(4-Methoxyphenyl)-3-(fluoromethoxy)benzene (2m, 110.2 mg, yield 95%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.52-7.50 (m, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.30-7.25 (m, 2H), 7.03-6.96 (m, 3H), 5.75 (d, J = 54.6 Hz, 2H), 3.84 (s, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ = -148.0 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 159.4, 157.2 (d, J = 3.0 Hz), 142.7, 133.0, 130.0, 128.2, 122.0, 115.2, 114.7, 114.3, 100.9 (d, J = 217.2 Hz), 55.4. HRMS (ESI-TOF) m/z: Calcd for C14H14FO2 [M+H]+: 233.0978; Found: 233.0974. GC-MS (EI, m/z): [M]+ 232.1. Methyl 4-(fluoromethoxy)benzoate (2n, 75.0 mg, yield 82%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 8.05-8.01 (m, 2H), 7.12-7.09 (m, 2H), 5.76 (d, J = 53.9 Hz, 2H), 3.90 (s, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ = -150.2 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 166.5, 160.1 (d, J = 2.9 Hz), 131.7, 125.3, 116.0, 99.9 (d, J = 219.3 Hz), 52.0. GC-MS (EI, m/z): [M]+ 183.0. The spectral data are consistent with those previously reported in the literature.11a 1-(Fluoromethoxy)-4-nitrobenzene (2p, 51.2 mg, yield 60%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 8.26-8.24 (m, 2H), 7.19-7.17 (m, 2H), 5.80 (d, J = 53.4 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = 151.5 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 161.1 (d, J = 2.9 Hz), 143.5, 126.0, 116.4 (d, J = 1.7 Hz), 100.1 (d, J = 221.2 Hz). GC-MS (EI, m/z): [M]+ 170.8. The spectral data are consistent with those previously reported in the literature.11a 5-(Fluoromethoxy)benzo[b]thiophene23 (2r, 83.7 mg, yield 92%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.76 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 5.4 Hz, 1H), 7.11 (dd,

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J = 8.7 Hz, 2.2 Hz, 1H), 5.74 (d, J = 54.8 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -148.0 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 154.6 (d, J = 3.0 Hz), 140.7, 135.0, 128.2, 123.7, 123.4, 115.6 (d, J = 1.2 Hz), 110.3, 101.5 (d, J = 217.1 Hz). HRMS (EI-Orbitrap) m/z: Calcd for C9H7FOS [M]+ ：182.02016; Found: 182.01975. GC-MS (EI, m/z): [M]+ 182.0. (4-(Fluoromethoxy)indolin-1yl)(phenyl)methanone (2s, 77.0 mg, yield 90%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 8.08 (brs, 1H), 7.55-7.44 (m, 5H), 7.14 (brs, 1H), 6.79 (d, J = 7.4 Hz, 1H), 5.73 (d, J = 54.4 Hz, 2H). 4.11 (m, 2H), 3.10 (t, J = 8.4 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -148.2 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 169.1, 153.0, 144.4, 136.8, 130.4, 129.0, 128.6, 127.1, 121.5, 112.6, 110.0, 100.5 (d, J = 218.4 Hz), 50.9, 25.1. HRMS (ESI-TOF) m/z: Calcd for C16H15FNO2 [M+H]+: 272.1087; Found: 272.1084. 2-(Fluoromethoxy)-1-(2(fluoromethoxy)naphthalen-1-yl)naphthalene (2u, 173.3 mg, yield 99%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 8.00 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.59-7.56 (dd, J = 9.0 Hz, 0.8 Hz, 2H), 7.427.38 (m, 2H), 7.28-7.23 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.51 (d, J = 54.9 Hz, 4H). 19F NMR (376 MHz, CDCl3, ppm): δ = -146.5 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 152.2 (d, J = 3.0 Hz), 133.6, 130.6, 130.2, 128.1, 126.9, 125.6, 124.9, 121.2 (d, J = 1.9 Hz), 117.3, 101.6 (d, J = 217.9 Hz). HRMS (ESI-TOF) m/z: Calcd for C22H16F2O2Na [M+Na]+: 373.1016; Found: 373.1006. GC-MS (EI, m/z): [M]+ 350.1. 1-Bromo-2-((fluoromethoxy)methyl)benzene23 (2v, 108.4 mg, yield 99%): yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.56 (dd, J = 8.0 Hz, 1.0 Hz, 1H), 7.48 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.35-7.31 (m, 1H), 7.20-7.16 (m, 1H), 5.40 (d, J = 56.0 Hz, 2H), 4.86 (d, J = 1.6 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -151.69 (s). 13 C NMR (100 MHz, CDCl3, ppm): δ = 136.1, 132.7, 129.5, 129.4, 127.5, 122.8, 103.3 (d, J = 213.6 Hz), 71.5. HRMS (EI-Orbitrap) m/z: Calcd for C8H8BrFO [M]+ ： 217.97426, 219.97221; Found: 217.97383, 219.97170. GCMS (EI, m/z): [M]+ 218.0，220.0 (R)-methyl-2-benzamido-3-(4(fluoromethoxy)phenyl)propanoate (2x, 149.0 mg, yield 90%). white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.74-7.72 (m, 2H), 7.52-7.49 (m, 1H), 7.447.40 (m, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 7.3 Hz, 1H), 5.68 (d, J = 54.6 Hz, 2H), 5.08-5.04 (m, 1H), 3.76 (s, 3H), 3.29-3.16 (m, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ = -148.53 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 172.0, 166.9, 156.0 (d, J = 2.9 Hz), 133.8, 131.8, 131.0, 130.6, 128.7, 127.0, 116.8, 100.7 (d, J = 217.2 Hz), 53.6, 52.4 (d, J = 3.0 Hz), 37.1. HRMS (ESI-TOF) m/z: Calcd for C18H19FNO4 [M+H]+: 332.1298; Found: 332.1299. (8S,9S,13S,14S)-3-(fluoromethoxy)-13-methyl7,8,9,11,12,13,14,15,16,17-decahydro-6H-

cyclopenta[a]phenanthrene (2y, 132.5 mg, yield 92%): white foam. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.29 (d, J = 8.6 Hz, 1H), 6.90 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 5.71 (d, J = 55.0 Hz, 2H), 2.97-2.85 (m, 2H), 2.35-2.22 (m, 2H), 1.98-1.90 (m, 2H), 1.85-1.66 (m, 3H), 1.60-1.15 (m, 8H), 0.78 (s, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ = -147.51 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 154.7 (d, J = 2.9 Hz), 138.6, 136.1, 126.6, 116.8, 114.0, 101.0 (d, J = 216.6 Hz), 53.6, 44.1, 41.1, 40.5, 39.1, 38.8, 29.9, 28.0, 26.8, 25.3, 20.6, 17.6. HRMS (EI-Orbitrap) m/z: Calcd for C19H25FO [M]+： 288.18894; Found: 288.18814. GC-MS (EI, m/z): [M]+ 288.0. 2-(Fluoro-d2-methoxy)naphthalene23 (2z, 88.2 mg, yield 99%). white foam. 1H NMR (400 MHz, CDCl3, ppm): δ= 7.81-7.76 (m, 3H), 7.49-7.38 (m, 3H), 7.24 (dd, J = 8.5 Hz, 2.5 Hz, 1H). 19F NMR (376 MHz, CDCl3, ppm): δ = -150.10 - -150.19 (m). 13C NMR (100 MHz, CDCl3, ppm): δ = 154.6, 134.2, 130.3, 129.8, 127.7, 127.3, 126.7, 124.8, 118.5 (d, J = 1.1 Hz), 111.1, 100.9 (m). HRMS (EI-Orbitrap) m/z: Calcd for C11H7D2FO [M]+ ： 178.07630; Found: 178.07567. GC-MS (EI, m/z): [M]+ 178.1. 1-Bromo-4-(d2-fluoromethoxy)benzene 23 (2ab, 82.4 mg, 80% yield): yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.46-7.41 (m, 2H), 6.98-6.94 (m, 2H). 19 F NMR (376 MHz, CDCl3, ppm): δ= -150.40 - -150.50 (m). 13C NMR (100 MHz, CDCl3, ppm): δ = 155.9, 132.6, 118.5 (d, J = 1.0 Hz), 116.1, 100.7 (m). HRMS (EI-Orbitrap) m/z: Calcd for C7H4D2BrFO [M]+： 205.97116, 207.96911; Found: 205.97073, 207.96854. GC-MS (EI, m/z): [M]+ 206.0, 208.0 (8S,9S,13S,14S)-3-(fluoro-d2-methoxy)-13-methyl7,8,9,11,12,13,14,15,16,17-decahydro-6Hcyclopenta[a]phenanthrene (2ac, 133.4 mg, yield 92%): white solid. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.27 (d, J = 8.5 Hz, 1H), 6.88 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 2.93-2.83 (m, 2H), 2.33-2.21 (m, 2H), 1.96-1.88 (m, 2H), 1.80-1.65 (m, 3H),1.58-1.13 (m, 8H), 0.77 (s, 3H). 19F NMR (376 MHz, CDCl3, ppm): δ = -148.86- -148.95 (m). 13C NMR (100 MHz, CDCl3): δ = 154.6 (d, J = 2.6 Hz), 138.5, 136.1, 126.6, 116.7, 114.0, 101.0 (m), 53.6, 44.1, 41.1, 40.5, 39.1, 38.8, 29.9, 28.0, 26.7 25.2, 20.6, 17.6. HRMS (ESI-TOF) m/z: Calcd for C19H24D2FO [M+H]+: 291.2093; Found: 291.2084. GC-MS (EI, m/z): [M]+ 290.0. (Fluoromethyl)((naphthalen-2yloxy)methyl)sulfane (3a): yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.79-7.76 (d, J = 8.7 Hz, 2H), 7.75-7.73 (d, J = 8.1 Hz, 1H), 7.48-7.43 (m, 1H), 7.39-7.35 (m, 1H), 7.21-7.20 (m, 2H), 5.65 (d, J = 52.2 Hz, 2H ), 5.41 (d, J =1.4 Hz, 2H). 19F NMR (376 MHz, CDCl3, ppm): δ= -148.8 (s). 13C NMR (100 MHz, CDCl3, ppm): δ = 154.4, 134.2, 129.8, 129.6, 127.7, 127.0, 126.6, 124.4, 118.9, 109.1, 84.4 (d, J = 214.9 Hz), 68.4 (d, J = 2.2 Hz). HRMS (EIOrbitrap) m/z: Calcd for C12H11FOS [M]+：222.05146; Found: 222.05078. GC-MS (EI, m/z): [M]+ 221.8.

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■ASSOCIATED CONTENT Supporting Information

The Supporting Information is available free of charge on the ACS Publications website NMR spectra of the products (PDF)

■AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected].

■ACKNOWLEDGMENT We are grateful to the National Natural Science Foundation of China (21172200) and Technology Research and Development Funds of Zhengzhou (141PRCYY516) for financial support.

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