CuI-Catalyzed Fluorodesulfurization for the Synthesis of Monofluoromethyl Aryl Ethers

Article abstract of DOI:10.1021/acs.joc.7b01438

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 substrate scope, and a high synthesis efficiency.

Full text of DOI:10.1021/acs.joc.7b01438

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Article
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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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,* ,†
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†The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450052, People’s Repub-
lic 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
O
1) broad substrates scope
CuI, DAST
2) good functional group tolerance
3) suitable for deuterated compounds
up to 28 examples and 99% yield
O
F
O
S
Ar
Ar
CH2Cl2, rt, 18 h
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 sub-
strates scope and high synthesis efficiency.
dation reaction using peroxide. In addition, when using this
■ INTRODUCTION
method to synthesize other monofluoromethyl aryl ethers in
our new drug development research, the reaction yields were
Fluoromethyl aryl ethers are of significant importance for the
materials, agricultural and pharmaceutical industries.1 For
not satisfactory.
examples, the monofluoromethyl aryl ethers play a conspicu-
Scheme 1. Methods for the Synthesis of Monofluoro-
methyl Aryl Ethers.
ous and increasingly important role in medical imaging filed,
which are widely used as PET (Positron Emission Tomogra-
phy) and SPECT (Single-Photon Emission Computed Tomog-
raphy) radiotracers.2 For half a century, various methods to
form monofluoro-, difluoro- and trifluoromethyl ethers have
been developed.3, 4 Among them, most of the reported syn-
thesis strategies for monofluoromethyl aryl ethers usually
use the following methods (Scheme 1). (1) Direct monofluo-
romethylation of alkoxides with monofluoromethylation
reagents such as FCH2Cl,5 FCH2Br,6 FCH2I7 and
PhSO(NTs)CH2F.8 (2) Halogen exchange reaction using KF
Previous work
O
fluoromethylation
(1)
fluorodecarboxylation
(4)
R
R
R
OH
O
R
R
O
O
OH
S
X
F
halogen-F-exchange
(2)
R
O
fluorodesulfurization
(5)
O
S
OH
oxidative fluorination
(3)
R
O
This work
O
9
CuI, DAST
and TBAF as fluoride sources. (3) Oxidative fluorination of
O
F
O
S
Ar OH
Ar
Ar
10
CH2Cl2, rt
benzylic
alcohols
with
XeF2
and
p-
trifluoromethylphenyl(difluoro)-λ-3-bromane.11 (4) Fluorode-
carboxylation of alkoxyacetic acids using XeF2, NFSI13 and
12
Metal containing Lewis acids are sometimes used as catalysts
selectfluor14, 15 as fluoride reagents. (5) Fluorodesulfurization,
18
for the fluorination reaction. For instances, ZnI2 was used
for examples, XeF2 and IF5-pyridine-HF17 were used in the
16
together with DAST to synthesize α-fluoro thioethers, and
SbCl3 was introduced to promote the fluorodesulfurization
for the preparation of trifluoromethyl aryl ethers.19 There-
fore, we tried to introduce metal containing Lewis acids to
the Benneche’s fluorodesulfurization system. Herein, an effi-
cient CuI catalyzed fluorodesulfurization for the synthesis of
monofluoromethyl aryl ethers using DAST as fluoride
sources was reported.
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
firstly reported by Benneche and co-workers9b in 1999. How-
ever, this method needs long reaction time and only three
substrates were reported. Particularly, the sulphoxide deriva-
tives are prepared from methylthiomethyl ethers via an oxi-
■ RESULTS AND DISCUSSION
Table 1. Screening Reaction Conditions a
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O
S
Scheme 2. CuI Catalyzed Fluorodesulfurization for
O
F
O
S
F
O
DAST (2.0 equiv), catalyst (x mol %)
CH2Cl2, rt, time
the Synthesis of Monofluoromethyl Aryl Ethers.a,b, c
1
+
2
3
1a
2a
3a
O
Method A: 20 mol% CuI, 2.0 eq.DAST
O
F
O
S
Ar
Ar
Method B: 2.0 eq.DAST
4
5
6
7
8
9
1a-1y
2a-2y
entry catalyst
x
time (h)
yield(%)b
O
F
2a
28
65
80
58
94
85
90
96
20
10
3a
55
25
O
F
O
F
O
F
Br
COOEt
1
--
--
18
36
18
18
18
18
18
18
18
18
18
18
18
18
18
12
8
2a
A: 99%; B: 28%b
2b
A: 95%; B: 24%b
2c
A: 99%; B: 29%b
2d
A: 89%; B: 28%b
2
--
--
n. dc
O F
O
F
O
F
O
F
3
AlCl3
SnCl2
ZnI2
ZnCl2
CuCl
CuI
10
10
10
10
10
10
10
NC
10
11
12
13
14
15
16
17
18
19
20
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Cl
Br
4
n. d
trace
trace
trace
trace
36
2gd
O
2e
A: 65%b; B: 12%b
2f
2h
A: 98%b, 80%; B: 40%b
A: 95%b
A: 90%; B: 25%b
O
5
B: 38%b; 88%b (36 h)
F
O
F
Ph
Br
O
F
6
Br
Br
F
O
F
7
2i
2j
2k
A: 60%b; B: 16%b
2l
A: 95%b, 67%; B: 34%b
A: 80%b, 36%; B: 21%b
A: 99%; B: 41%b
8
O
O
F
O
F
O
O
F
9
Cu2O
O
F
O
NO2
OHC
O
10
11
12
13
14
15
16
17
Cu(OAc)2 10
Cu(NO3)2 10
Pd(OAc)2 10
68
2m
A: 95%; B: 38%b
2o
A: 60%b; B: 12%b
2p
A: 75%b, 60% (48 h)
B: 15%b (48 h)
2n
A: 91%b, 82%; B: 40%b
8
60
O
F
F
O
F
O
F
O
F
25
90
93
59
NO2
N
Bz
S
N
2q
A: 40%b, 48 h
B: 0%b, 48 h
CuI
CuI
CuI
CuI
CuI
1
trace
trace
n.d.
n.d.
n.d.
2r
A: 92%; B: 29%b
2s
A: 90%; B: 28%b
2t
A: 0%b; B: 0%b
5
O
20
30
50
99/99c
O
Br
O
F
F
O
O
F
NHBz
O
F
O
F
O
94
2u
A: 99%; B: 23%b
2v
A: 99%; B: 52%b
2w
A: 99%b; B:48%b
2x
A: 90%; B: 35%b
90
aReaction conditions: 1a (0.5 mmol), DAST (1.0 mmol), 2.5
mL of CH2Cl2, 25 °C. bYields were determined by 19F NMR
spectroscopy with 2-(4-(trifluoromethyl)phenyl) acetonitrile
as a standard. cIsolated yield. n.d. = no detected.
F
H
H
O
2y
A: 92%; B: 40%b
aStandard 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
Firstly, compound 1a (prepared from naphthalen-2-ol and
chloro(methylsulfinyl)methane20) (see Experimental Sec-
tion) was treated with DAST (2.0 equiv) at room tempera-
ture for 18 hours, 55% yield of 3a was detected, with only 28%
yield of the desired product 2a (Table 1, entry 1) which was
determined by 19F NMR spectroscopy. The compound 3a is
analogous to the side product reported by the group of
Benneche in 1996.16 The mechanism of this side reaction is
similar to the Pummerer rearrangement.18, 21 Prolonging the
reaction time to 36 hours, the yield of 2a was increased to
65% (entry 2) accompanied with 25% yield of 3a. Then, vari-
ous 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 con-
ducive to the reaction. Thus, the optimum reaction condi-
tions were determined as the combination of 1.0 equiv of 1a,
20 mol % of CuI, 2.0 equiv DAST, in DCM at room tempera-
ture for 18 hours.
DAST was 2.0 mmol). Yields were determined by 19F NMR
b
spectroscopy with 2-(4-(trifluoromethyl)phenyl) acetonitrile
c
as standard. Isolated yield. dCompound 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 condi-
tions. The reaction proceeded smoothly to give the mono-
fluoromethyl naphthyl ethers in moderate to good yields.
When using the methylsulfinylmethyl ethers substituted at
the α and β position of naphthalene, the fluorodesulfuriza-
tion reactions afforded the desired products (2a and 2b) in
99% and 95% isolated yields, respectively. Substrates con-
taining naphthalene with electron-withdrawing groups were
also transformed into monofluoromethoxy compounds (2c,
2d, 2f) in high yields. The fluorodesulfurization reaction oc-
curred on the substrates with benzene rings and gave the
various monofluoromethyl phenyl ethers 2g-2q in 40-99%
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yields. Substrates containing ketones and aldehydes are sen-
Scheme .4. Scalability of the Fluorodesulfurization of
1c
1
2
3
4
5
6
7
8
sitive to DAST, but the reaction were also found to give 2e
and 2o in 65% and 60% yields detected by 19F NMR spectros-
copy, respectively. The structures of crude 2e and 2o were
O
F
1
confirmed by H NMR, 19F NMR and GC-MS. The method
0.2 equiv CuI, 2.0 equiv DAST
CH2Cl2, rt,18 h
99%
O
S
Br
Br
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 mole-
cule was also successful by using 4.0 eq. DAST and the de-
sired product 2u was obtained in 99% yield. Monofluorome-
thyl benzyl ether such as 2v and 2w were obtained in 99%
yield, which were sensitive to the moisture. We further ap-
plied this method to more complex organic molecules. For
examples, under the standard conditions, monofluorometh-
oxy group containing compounds 2x and 2y were obtained in
90% and 92% yields. Among them, 2x is an intermediate of
potential PET tracer for imaging amino acid transport,2a and
compound 2y contains a steroid ring would be a potential
antiproliferative agent.2b The contrast experiments between
the two methods shows that the fluorodesulfurization with-
out CuI has low efficiency for most of the substrates. Particu-
larly, 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, re-
spectively.
2c
O
2.54 g
(9.96mol)
Br
O
F
28%
1c
2.0 equiv DAST
CH2Cl2, rt,18 h
3.00 g
(10 mmol)
9
2c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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60
0.72 g
(2.82 mmol)
The CuI catalyzed fluorodesulfurization method is also suit-
able for the application in grams scale experiment (Scheme
4). Under the standard reaction conditions, 2.54 g of com-
pound 2c was obtained in 99% yield from 3.00 g of 1c. For a
comparison, the fluorodesulfurization without catalyst pro-
vided 0.72 g of product 2c in 28% yield.
■CONCLUSION
In summary, the introduction of CuI to an old fluorodesulfu-
rization system improves the reaction process, provides an
efficient approach for the synthesis of monofluoromethyl aryl
ethers. This method exhibits a good functional group toler-
ance 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 mono-
fluoromethyl aryl ethers and for the larger scale application.
Scheme 3. Application for Preparing Deuterated Mono-
fluoromethyl Aryl Ethers.a,b,c
O
D
D
D
D
D
D
20 mol% CuI, 2.0 eq DAST
O
S
D
O
F
Ar
Ar
■EXPERIMENTAL SECTION
1z-1ab
2z-2ab
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 mi-
cro Melting point Measurement Instruments, thermometer
was unrevised. The transformation progress and Mass spec-
tra were indicated by LC-MSD-Trap-XCT instrument or GC-
MS (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 car-
bon resonances at 400, 376 and 100 MHz, respectively.
F
F
O
O
D
D
D
F
D
D
H
H
Br
D
O
2z
99%, 99.5 atom%D
2ab
80%, 99.5 atom%D
2ac
92%, 99.5 atom%D
aStandard reaction conditions: 1 (0.5 mmol), CuI (20 mol %),
DAST (1.0 mmol) in 2.5 mL of CH2Cl2 at 25 °C for 18 h. bI-
solated yield. cDeuterium content was determined by 1H
NMR spectroscopy.
Introduction of deuterium into organic pharmaceutical mol-
ecules offers potential benefits, such as improving exposure
profiles and decreasing production of toxic metabolites.22
The approaches of introducing OCD2F group into organic
molecules were rarely reported. To date, only two methods
were reported using CD2I2 and CD2BrF2d as deuterium
2c
sources. Our protocol was attempted to prepare deuterated
monofluoromethyl aryl ethers. Reactions occurred on deu-
terated 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.
General procedure for the synthesis of substrates20 So-
dium hydride (480 mg, 12 mmol, 60% in mineral oil) was
added to a solution of phenol (10 mmol) (or benzyl alco-
hol) in dry DMF (10 mL) at 0 oC under argon atmosphere.
3
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After 30 min, potassium iodide (1.99 g, 12 mmol), chlo- 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
2
3
4
5
6
7
8
ro(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
1-((methylsulfinyl)methoxy)-4-chlorobenzene (1g,
1
1.75 g, yield 78%):yellow solid; mp 65-67 °C; H NMR (400
1
pure products. The products were characterized by H
MHz, CDCl3, ppm): δ = 7.28-7.26 (m, 2H), 7.00-6.99 (m,
NMR, 13C NMR, HRMS and LC-MS.
2H), 4.97 (d, J = 10.3 Hz, 1H), 4.90 (d, J = 10.3 Hz, 1H), 2.68
9
13
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
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51
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55
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57
58
59
60
(s, 3H). C 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
2-((Methylsulfinyl)methoxy)naphthalene23 (1a, 1.76
1
g, yield 80%): white solid; mp 103-104 °C; H 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)-4-bromobenzene. (1h,
1
1.98 g, yield 80%): white solid; mp 71-72 °C; H 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
13
(s, 3H). C 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 previ-
ously reported in the literature.24
1-((Methylsulfinyl)methoxy)naphthalene23 (1b, 1.72 g,
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
yield 78%): white solid; mp 55-56 °C; H 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)-6-
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), 6.99-
6.94 (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 (ESI-
TOF) 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.
bromonaphthalene23 (1c, 2.53 g, yield 85%): white solid;
1
mp 105-106 °C; H 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.
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.
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
13
(q, J = 7.1 Hz, 2H), 2.82 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). C
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.
1-((Methylsulfinyl)methoxy)-3-(4-
methoxyphenyl)benzene23 (1m, 2.32 g, yield 84%): white
1
solid; mp 99-101 °C; H NMR (400 MHz, CDCl3, ppm): δ =
6-((Methylsulfinyl)methoxy)naphthalene-2-
carbonitrile23 (1f, 1.72 g, yield 70%):brown solid; mp 135-
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
1
136 °C; H NMR (400 MHz, CDCl3, ppm): δ = 8.16 (s, 1H),
13
(d, J = 10.1 Hz, 1H), 3.85 (s, 3H), 2.71 (s, 3H). C NMR (100
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),
MHz, CDCl3, ppm): δ = 159.5, 157.8, 142.9, 132.8, 130.1, 128.2,
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The Journal of Organic Chemistry
hydrous Na2SO4, concentrated, and purified by flash col-
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.
umn 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 reac-
tion mixture was cooled to room temperature and ex-
tracted 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
2
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 (ESI-
TOF) m/z: Calcd for C10H13O4S [M+H]+: 229.0535; Found:
229.0533. LC-MS (ESI, m/z): [M+H]+ 229.1.
3
4
5
6
7
8
9
13
1H NMR, C NMR, HRMS and LC-MS. The atom% D was
determined by 1H NMR.
10
11
12
13
14
15
16
17
18
19
20
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22
23
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60
1-((Methylsulfinyl)methoxy)-4-nitrobenzene23 (1p,
2-((d5-Methylsulfinyl)methoxy)naphthalene23 (1z,
1
1
1.40 g, yield 65%): yellow solid; mp 129-130 °C; H NMR
1.80 g, yield 80%): white solid; mp 105-106 °C; H 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
(400 MHz, CDCl3, ppm): δ = 7.81-7.76 (m, 3H), 7.50-
7.46 (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 (ESI-
TOF) 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)-4-
1
(1r, 1.81 g, yield 80%): white solid; mp 79-79 °C; H NMR
(400 MHz, CDCl3, ppm): δ = 7.76 (d, J = 8.8 Hz, 1H), 7.48-
7.46 (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.
bromobenzene23 (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.
(4-((Methylsulfinyl)methoxy)indolin-1-
yl)(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)-2-
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 moni-
tored 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.
bromobenzene23 (1v, 1.71 g, yield 65%): yellow oil. H
1
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 (ESI-
TOF) 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), d5-
chloro(methylsulfinyl)methane (1.40 g, 12 mmol) was add-
ed, 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-
The products were characterized by 1H NMR, 13C NMR, 19
NMR, HRMS and GC-MS.
F
2-(Fluoromethoxy)naphthalene (2a, 87.0 mg, yield
1
99%): white foam. H 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,
13
ppm): δ = -148.8 (s). C 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 spec-
tral data are consistent with those previously reported
in the literature.5
1-(Fluoromethoxy)naphthalene (2b, 83.6 mg, yield
1
95%): white foam. H 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
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
(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
1
2
3
4
5
6
7
8
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.
2-Bromo-6-(fluoromethoxy)naphthalene25
(2c,
1
9
125.7 mg, yield 99%): white foam. H 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. GC-
MS (EI, m/z): [M]+ 254.0, 256.0
10
11
12
13
14
15
16
17
18
19
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23
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60
1-Phenyl-4-(fluoromethoxy)benzene (2l, 100.0 mg,
1
yield 99%): white foam. H NMR (400 MHz, CDCl3,
ppm): δ = 7.55-7.52 (m, 4H), 7.42-7.39 (m, 2H), 7.33-
7.29 (m, 1H), 7.14-7.11 (m, 2H), 5.72 (d, J = 54.6 Hz, 2H).
19F 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
Ethyl
3-(fluoromethoxy)naphthalene-2-
carboxylate23 (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.
1-(4-Methoxyphenyl)-3-(fluoromethoxy)benzene
1
(2m, 110.2 mg, yield 95%): white foam. H 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,
13
ppm): δ = -148.0 (s). C 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,
6-(Fluoromethoxy)naphthalene-2-carbonitrile23
1
(2f, 111.7 mg, yield 90%): white foam. H 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
yield 82%): white foam. H 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-Bromo-4-(fluoromethoxy)benzene. (2h, 81.6 mg,
1
yield 80%): yellow oil. H NMR (400 MHz, CDCl3,
1-(Fluoromethoxy)-4-nitrobenzene (2p, 51.2 mg,
1
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 re-
ported 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 =
yield 60%): white foam. H 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,
1
yield 92%): white foam. H 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,
6
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J = 8.7 Hz, 2.2 Hz, 1H), 5.74 (d, J = 54.8 Hz, 2H). 19F
cyclopenta[a]phenanthrene (2y, 132.5 mg, yield
92%): white foam. H NMR (400 MHz, CDCl3, ppm): δ
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.
1
1
2
3
4
5
6
7
8
= 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
13
NMR (376 MHz, CDCl3, ppm): δ = -147.51 (s). C 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.
(4-(Fluoromethoxy)indolin-1-
yl)(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.
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21
22
23
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60
2-(Fluoro-d2-methoxy)naphthalene23 (2z, 88.2 mg,
1
yield 99%). white foam. H 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]+
2-(Fluoromethoxy)-1-(2-
(fluoromethoxy)naphthalen-1-yl)naphthalene (2u,
1
173.3 mg, yield 99%): white foam. H 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), 7.42-
7.38 (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,
178.1.
23
1-Bromo-4-(d2-fluoromethoxy)benzene
(2ab,
1
82.4 mg, 80% yield): yellow oil. H NMR (400 MHz,
CDCl3, ppm): δ = 7.46-7.41 (m, 2H), 6.98-6.94 (m, 2H).
19F NMR (376 MHz, CDCl3, ppm): δ= -150.40 - -150.50
13
ppm): δ = -146.5 (s). C 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.
13
(m). C 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-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-
1-Bromo-2-((fluoromethoxy)methyl)benzene23 (2v,
1
108.4 mg, yield 99%): yellow oil. H 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).
13C 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
cyclopenta[a]phenanthrene (2ac, 133.4 mg, yield
1
92%): white solid. H 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):
(EI-Orbitrap)
m/z: Calcd for C8H8BrFO [M]+ ：
13
217.97426, 219.97221; Found: 217.97383, 219.97170. GC-
MS (EI, m/z): [M]+ 218.0，220.0
δ = -148.86- -148.95 (m). C 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.
(R)-methyl-2-benzamido-3-(4-
(fluoromethoxy)phenyl)propanoate (2x, 149.0 mg,
1
yield 90%). white foam. H NMR (400 MHz, CDCl3,
ppm): δ = 7.74-7.72 (m, 2H), 7.52-7.49 (m, 1H), 7.44-
7.40 (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.
(Fluoromethyl)((naphthalen-2-
yloxy)methyl)sulfane (3a): yellow oil. H NMR (400
1
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 (EI-
Orbitrap) m/z: Calcd for C12H11FOS [M]+：222.05146;
Found: 222.05078. GC-MS (EI, m/z): [M]+ 221.8.
(8S,9S,13S,14S)-3-(fluoromethoxy)-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-
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■ASSOCIATED CONTENT
1
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Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website
NMR spectra of the products (PDF)
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■AUTHOR INFORMATION
Corresponding Author
9
*E-mail: zdp@zzu.edu.cn.
*E-mail: wyj@zzu.edu.cn.
*E-mail: yusheng.wu@tetranovglobal.com.
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■ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation
of China (21172200) and Technology Research and Develop-
ment Funds of Zhengzhou (141PRCYY516) for financial sup-
port.
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