Difluoromethylation of Phenols and Thiophenols with the S-(Difluo-romethyl)sulfonium Salt: Reaction, Scope, and Mechanistic Study

Article abstract of DOI:10.1021/acs.joc.9b02424

A facile and practical approach for the difluoromethylation of phenols and thiophenols was described. Making use of the recently developed bench-stable S-(difluoromethyl)sulfonium salt as the difluorocarbene precursor, a wide variety of diversely functionalized phenols and thiophenols were readily converted to their corresponding aryl difluoromethyl ethers in good to excellent yields in the presence of lithium hydroxide. Chemoselectivity of various O,S-nucleophiles toward difluorocarbene was systematically studied, suggesting the reactivity order ArS- > RS-, ArO- > ROH > RO-, ArSH, ArOH, RSH.

Full text of DOI:10.1021/acs.joc.9b02424

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Article
Difluoromethylation of Phenols and Thiophenols with S-
(Difluoromethyl)sulfonium Salt: Reaction, Scope and Mechanistic Study
Guo-Kai Liu, Wen-Bing Qin, Xin Li, Li-Ting Lin, and Henry Nai Ching Wong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02424 • Publication Date (Web): 24 Oct 2019
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The Journal of Organic Chemistry
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Difluoromethylation of Phenols and Thiophenols with S-(Difluo-
romethyl)sulfonium Salt: Reaction, Scope and Mechanistic Study
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Guo-Kai Liu,*†a Wen-Bing Qin,†a Xin Li,a Li-Ting Lin a and Henry N. C. Wongb
a School of Pharmaceutical Sciences, Shenzhen University Health Science Centre, Shenzhen University, 3688 Nanhai Ave.,
Shenzhen 518060, China
b Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
Supporting Information
OCF2H
MeO
HF2C
OMe
OH
SH
Het
Het
R
Het
Het
R
R
S
+
OMe
BF4
SCF2H
R
1
ABSTRACT: A facile and practical approach for the difluoromethylation of phenols and thiophenols was described. Making use of
the recently developed bench-stable S-(difluoromethyl)sulfonium salt as the difluorocarbene precursor, a wide variety of diversely
functionalized phenols and thiophenols were readily converted to their corresponding aryl difluoromethyl ethers in good to
excellent yields in the presence of lithium hydroxide. Chemoselectivity of various O, S-nucleophiles toward difluorocarbene was
systematically studied, suggesting the reactivity order ArS＿ > RS＿, ArO＿ > ROH > RO＿ , ArSH, ArOH, RSH.
Generally, ArOCF2H and ArSCF2H are synthesized via O,
S-difluoromethylation of phenols and thiophenols, which
INTRODUCTION
Difluoromethoxy group (OCF2H) is an importantly structural
represents a routine strategy for the preparation of aryl
difluoromethyl (thio)ethers, although a few examples installed
these compounds by metal-catalyzed or visible light-promoted
difluoromethylthiolation and difluoromethoxylation using
difluoromethoxylating reagent and difluoromethylthiolating
reagents.10 Phenols are sufficiently acidic to form phenoxide
anions under strongly alkaline conditions, and phenoxide
anions react readily with difluorocarbenes generated in situ
from various reagents. In the past decades, many efforts have
been circumvented to develop reagents and protocols for this
purpose.11 Initially, the ozone-depleting substrates (ODS), i.e.,
motif, and have found widespread utility in pharmaceuticals1,
agrochemicals2
and
materials.3
Particularly,
Aryl
difluoromethyl ethers play important roles in medicinal
chemistry and drug discovery because the difluoromethyl
group is capable of serving as a bioisostere to CH3OH and SH
units,4 as well as a lipophilic hydrogen-bond donor.5 As
illustrated in Figure 1, aryl difluoromethyl ether moiety is
present in the selective phosphodiesterase type 4 (PDE 4)
inhibitor Roflumilast, used for treatment of chronic obstructive
pulmonary disease (COPD).6 Pantoprazole is popular as an
irreversible proton pumping inhibitor,7 while Garenoxacin is a
novel broad-spectrum quinolone antiseptic.8 It is noteworthy
that GRN-529, developed by Wyeth, is in clinical trials stage
for the treatment of autism in children.9 Therefore, the
development of practical, efficient approaches to aryl
difluoromethyl ethers remains attractive.
11b
11c
HCF2Cl,11a HCF3
and CF2Br2
were used for the
difluoromethylation of phenols. Afterwards, some non-ozone-
depleting substrates (NODS) difluorocarbene precursors have
been recorded for the synthesis of difluoromethyl ethers from
phenols, including FSO2CF2COOH,12a PhCOCF2Cl,12b
PhSO2CF2Cl,12c BrCF2P(O)(OEt)2,13a ClF2COONa,13b n-
Bu3N(CF2H)Cl,13c HCF2OTf,14a and BrCF2CO2Et.14b However,
these approaches employing ODS and NODS reagents
somewhat suffer from high reaction temperature, long reaction
time, and a narrow substrate scope. These reagents usually do
not tolerate a great deal of functional groups, thus limiting
their widespread applicability. To remedy these problems, Hu
revealed an efficient protocol using the commercially available
TMSCF2Br as a difluorocarbene source.15 Later, Xiao reported
Ph3P+CF2COO- (PDFA) as an efficient phosphonium ylide
reagent that also leads to difluoromethylation reaction of
phenols and thiophenols, though only a few simple examples
O
O
O
O
OH
HF2CO
N
N
S
O
N
HN
N
H
OCF2H
Pantoprazole
Garenoxacin
O
Cl
O
N
N
N
H
N
Cl
N
HF2CO
HF2CO
O
Roflumilast
GRN-529
Figure 1. Drugs containing OCF2H building block
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were demonstrated.16 As another possibility, our group has
develope
readily difluoromethylated to give good to high yields. A
broad range of functional groups, including nitro (4g-i),
sulfone (4j), ester (4l-n), aldehyde (4o-q), alkene (4s), alcohol
(4t), amine (4y), amide (4r, 4x), benzoyl (4k), and methoxy
1
2
3
Table 1. Survey of Reaction Conditionsa
MeO
OMe
4
5
6
7
8
9
Scheme 1. Difluoromethylation of phenols and thiophenolsa
Base
HF2C
Ph
OH
Ph
OCF2H
+
S
Solvent, Temp.
Ar, overnight
BF4
OMe
MeO
OMe
LiOH or NaH (2.2 equiv.)
fluorobenzen, rt or 10 o
XH
XCF2H
2a
1
4a
HF2C
R
Het
R
Het
+
S
C
entry
1
base (equiv)
LiOH (2.2)
LiOH (2.2)
LiOH (2.2)
LiOH (2.2)
LiOH (2.2)
LiOH (2.2)
solvent
toluene
temp (°C)
yield (%)
BF4
OMe
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
rt.
0
70
63
20
78
38
80
60
73
30
13
28
60
57
59
60
81
62
2 X=O
3 X=S
4 X=O
5 X=S
1
2
chlorobenzene
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
Ph
OCF2H
tBu
OCF2H nBu
OCF2H
PhO
OCF2H
4
DCM
c
c
c
c
4a
, 81%
4b
, 75%
4c
, 85%
4d
, 57%
5
CH3CN
OMe
OCF2H
OMe
6
fluorobenzene
fluorobenzene
fluorobenzene
fluorobenzene
fluorobenzene
fluorobenzene
fluorobenzene
fluorobenzene
fluorobenzene
fluorobenzene
fluorobenzene
fluorobenzene
Br
OCF2H
O2N
OCF2H
Me
O2N
OCF2H
7
KOH (1.0 M, 2.2)
NaH (2.2)
8
c
c
b
b
4e
, 43%
4f
4g
4k
4o
4h
, 52%
, 66%
, 69%
9
K3PO4 (2.2)
NaOAc (2.2)
Cs2CO3 (2.2)
LiOH (1.6)
LiOH (3.0)
LiOH (2.2)
LiOH (2.2)
NaH (2.2)
O
S
Cl
OCF2H Me
OCF2H Bz
OCF2H MeO2C
OCF2H
10
11
12
13
14
15
16
17
O
O2N
4i
b
b
c
b
4j
, 45%
, 72%
4l
, 70%
, 90%
MeO2C
OCF2H MeO2C
OCF2H OHC
OCF2H
OCF2H
Br
4m
, 61%
I
, 66%b (69%)d
OHC
4p
b
b
b
, 46%
4n
, 59%
10
10
0
OMe
OCF2H
HO
OCF2H
Br
OCF2H AcHN
CHO
OCF2H
NaH (2.2)
a Reaction conditions (unless otherwise specified): 2a (0.2 mmol), 1 (1.2
equiv, 0.24 mmol), fluorobenzene (2.0 mL), rt, overnight, isolated yields.
-d bench-stable sulfonium salts 1, which we have employed as
a highly effective difluoromethylating reagent for C-selective
difluoromethylation of β-ketoesters and malonates,17a and also as
a difluorocarbene precursor for O-difluoromethylation of
b
b
c
c
4q
4u
4r
4s
4t
, 62%
, 41%
, 62%
, 52%
OCF2H
Br
OCF2H
OCF2H
O
N
OCF2H
H
b
b
c
b
4v
4z
4w
5a
4x
5b
, 65%
, 71%
, 45%
, 43%
OCF2H
OCF2H
MeO
aliphatic alcohols involving
a five-membered transition
SCF2H
Br
SCF2H
state.17b Herein we examined whether sulfonium salt 1 can
react with phenols and thiophenols under mild conditions to
furnish diverse aryl difluoromethyl (thio)ethers.
N
H
O
O
b
b
b
c
, 86%
, 99%
4y
, 56%
, 74%
Cl
Cl
SCF2H
O2N
SCF2H
AcHN
SCF2H
SCF2H
Cl
RESULTS AND DISCUSSION
Cl
Cl
b
b
b
b
5c
5g
5k
5d
5h
5e
5f
, 90%
, 61%
, 99%
, 95%
Reaction conditions were optimized using 4-phenylphenol
(2a) as a model substrate (Table 1). Thus, the reaction
smoothly occurred with the use of 2.2 equivalents of LiOH at
room temperature in toluene, affording difluoromethyl ether
4a in an isolated yield of 70% (entry 1). Subsequently, the
effect of various solvents was investigated (entries 2-6),
dichloromethane and arene solvents such as toluene,
chlorobenzene and fluorobenzene, were suitable solvents, with
fluorobenzene being proved to be the best (80%, entry 6).
Next, various bases were investigated and results clearly
showed that strong bases (entries 6-8) are superior to weaker
ones (entries 9-11). NaH gave a high yield (73%) as that of
LiOH (entry 8). Yield fell when the quantity of LiOH was
reduced to 1.6 or increased to 3.0 equivalents (entries 12-13).
Reaction temperature also showed influence on yields.
Reactions that were run at 0 °C and 10 °C led to lower yields
of 59 % and 60%, respectively (entries 14-15), but higher
yield of 81% was obtained at 10 °C in the presence of NaH
(entry 16).
N
N
N
SCF2H
SCF2H
SCF2H
SCF2H
N
H
S
N
b
b
b
b
5i
, 91%
5j
, 63%
, 76%
, 59%
N
S
N
O
SCF2H
SCF2H
b
b
5l
, 97%
, 99%
a
2
Reaction conditions: (0.2 mmol, 1.0 equiv), base (0.44 mmol, 2.2
1
equiv), (0.24 mmol, 1.2 equiv), fluorobenzene (2.0 mL), rt, over night.
b LiOH was used as a base. c NaH
4
.
Yields are for the isolated products
was used as a base, and the reaction proceed at 10 C. d5.0 mmol scale
with LiOH as a base. Me = methyl, MeO = methoxy, tBu = tert-butyl, Ac
= Acetyl, Bz = benzoyl, Ph = phenyl.
o
(4e) were compatible with this reaction. The reaction also
tolerated chloro, bromo and iodo substitutions at the para-
positions (4f, 4i) or ortho-positions (4m, 4n), which allows
further transformation through cross-coupling reactions.
Importantly, this protocol exhibited chemoselectivity in a
phenol bearing aliphatic alcohol (4t, 52%), alkene (4s, 62%),
implying that phenoxides are more reactive than aliphatic
alkoxides and alkenes in capturing difluorocarbene. Naphthols
2u-w also took part in difluoromethylation reaction, leading to
moderate to good yields. Remarkably, enol 2z also proved to
Using the optimized reaction conditions (entries 6 and 16,
Table 1), we then examined the scope of phenols for the
synthesis of various aryl difluoromethyl ethers. Both electron-
deficient (2f-q) and electron-rich phenols (2a-e, 2s-t) were
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The Journal of Organic Chemistry
O
O
be a suitable substrate, offering the desired product 4z in 74%
I
a
I
b
OMe
OMe
1
2
-
+
[CF2H]+BF4
yield. Heterocyclic compounds such as quinolinone, indole
and coumarin were also well tolerated in this reaction,
providing the desired products 4x, 4y and 4z in 43%, 56% and
74% yields, respectively.
69%
96.4%
H
O
HF2CO
2n,
5.0 mmol
1
1.2 eq
4n
3
4
5
6
7
8
9
O
O
c
d
The potential usage of this protocol was further
demonstrated in the difluoromethylation of thiophenols 3. As
shown in Scheme 1, under similar reaction conditions, S-
(difluoromethyl)sulfonium salt 1 exhibited better reactivity
with thiophenols than phenols, providing aryl difluoromethyl
thioethers in high to excellent yields in all cases, regardless of
whether the thiophenols containing electron-donating (4a, 4f)
or electron-withdrawing groups (4b, 4d, 4e). Importantly,
many heterocycles of pharmaceutical interest, including
pyridine, pyrimidine, thiophene, imidazole, oxazole and
thiazole were readily amenable under the mild reaction
N
N
OH
OMe
95.8%
83.7%
HF2CO
HF2CO
7
8
O
N
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
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40
41
42
43
44
45
46
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50
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59
60
N
N
HF2CO
GRN-529
2n
Reaction conditions: a)
(1.39 g, 5 mmol), LiOH (11.0 mmol, 2.2
1
equiv.) and fluorobenzene (20.0 mL), (6.0 mmol, 1.2 equiv.), rt,
conditions,
installing
medicinally
useful
overnight. b) 2-Ethynylpyridine (1.01 equiv.), Pd(PPh3)2Cl2 (1.0
difluoromethythiolated heterocy-
o
mol% ), CuI (2.0 mol%), NH4OH (8 equiv.), NMP, 40 C, 6 h. c)
NaOH (1.2 equiv.), H2O/CH3OH, 40-45 oC, 3hr. d) AcOH, H2O. d)
CDI (1.1 equiv), DIPEA (3.1 equiv.), NMP, 6,7-Dihydro-5H-
pyrrolo[3,4-b]pyridine dihydrochloride (1.05 equiv.).
Scheme
2.
Study
of
chemoselectivity
in
difluoromethylation of (thio)phenols and alcoholsa
a)
OH
OH
OCF2H
OCF2H
+
NaH (2.2 equiv.)
+
1
clic compounds (5g-l).
(1.2 equiv.)
PhF, 0 o
C
Subsequently, the chemoselectivity of this protocol as
demonstrated in 4t was studied further in order to give an
insight into chemoselectivity. Thus, the difluoromethylation of
2t was performed under the current condition, as well as under
that reported previously by us,17b leading to different results.
OH
, 0.1 mmol
overnight
OCF2H
52%
OCF2H
trace
OH
7%
2t
b)
OH
OH
OCF2H
OCF2H
+
LiOH (2.2 equiv)
+
1
(1.2 equiv)
＿
These results indicate that phenoxides (ArO ) are more
PhF, rt
reactive than aliphatic alkoxides (RO ＿ ) (Scheme 2a) and
aliphatic alcohols (ROH) (Scheme 2b). Furthermore, aliphatic
alcohols (ROH) are more reactive toward difluorocarbene than
phenols (ArOH) (Scheme 2c). In addition, consistent with
results shown in Scheme 1, thiophenoxide (ArS＿ ) can more
overnight
OH
, 0.1 mmol
OCF2H
36%
OCF2H
trace
OH
4%
2t
c)
OH
OH
OCF2H
OCF2H
+
NaOAc (5.0 equiv.)
1
(1.0 equiv.)
+
Bu4NBF4 (0.2 equiv)
CH2Br2/H2O (1:1)
rt., 24 h
OH
, 0.1 mmol
efficiently capture difluorocarbene than phenoxide (ArO ＿
)
OCF2H
0%
OCF2H
trace
OH
2t
24%
(Scheme 2d) when they coexisted in a reaction mixture. We
systematically investigated the reactivities of various O, S-
nucleophiles toward difluorocarbene (see Supporting
Information). Experimental results clearly suggest that the
order of reactivities of O, S-nucleophiles is ArS＿ > RS＿, ArO
＿ > ROH > RO＿ , ArSH, ArOH, RSH.
d)
SCF2H
OCF2H
+
OH
SH LiOH (2.2 equiv.)
1
(1.2 equiv.)
+
MeO
MeO
MeO
MeO
PhF, rt,
overnight
0.1 mmol
0.1 mmol
26%
43%
Scheme 3. Synthesis of the drug candidate GRN-529
To demonstrate the usefulness of this difluoromethylation
protocol, the synthesis of the drug candidate GRN-529 was
carried out (Scheme 3). As can be seen, difluoromethylation of
the easily available phenol 2n generated the key intermediate
4n in an isolated yield of 69%, which underwent stepwise
cross-coupling, hydrolysis (saponification) and amide
formation to produce GRN-529 in an overall yield of 53.5%.
According to the mechanism proposed previously,
difluoromethylation of phenols proceeds via reaction of
phenoxides with in situ generated difluorocarbene. In order to
gain more information and illustrate the plausible reaction
pathway, some control experiments were carried out. Thus, the
deuterated sulfonium salt [D]-1 gave the deuterated product [D]-
3a in a yield of only 11%, while 3a was generated in 59%
yield (Scheme 4a), suggesting that the reaction proceeds via a
difluorocarbene process. Consistent with this phenomenon,
addition of tetramethylethylene to the reaction expectedly
generated 3,3- difluoro-1,1,2,2-tetramethylcyclopropane 4 in
57% yield (Scheme 4b), which provides a solid evidence that
difluorocarbene was generated during this process. Therefore,
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on the basis of the experimental data mentioned above and
Page 4 of 9
ionization mode on an Agilent 1260-Infinity LC/MSD or a Q-
Exactive high resolution mass spectrometer. All solvents and
reagents were dried and purified by the usual techniques prior
to use. Commercially available reagents were used as
received. Reactions were monitored by TLC (detection with
UV light). Flash chromatography: silica gel (300-400 mesh).
1
2
3
4
5
6
7
literatures reported previously by other groups, we propose the
Scheme 4. Control experiments and plausible reaction
mechanism for difluoromethylation of (thio)phenols by 1a
a)
MeO
OMe
LiOH (2.0 equiv.)
PhF, rt, 30 min
Ph
Ph
OCF2H
OCF2D
3a
, 59%
DF2C
S
Difluoromethylation of Phenols 2 and Thiophenols 3 with
Electrophilic Difluoromethylating Reagent 1
Ph
OH
+
OMe
BF4
[D]-3a
, 11%
2a
[D]-1
General Procedure A: phenols 2 or thiophenols 3 (0.2 mmol,
1.0 equiv), LiOH (0.44 mmol, 2.2 equiv) and fluorobenzene
(2.0 mL) were added into a flame-dried Schlenk tube under
argon atmosphere and stirred at room temperature for 30 min.
Then 1 (0.24 mmol, 1.2 equiv) was added into the mixtures in
one portion directly, and the reaction was stirred under argon
atmosphere of argon at room temperature overnight. After
filtering through celite and removing the solvent in vacuum,
the residue was purified by flash column chromatography on
silica gel to obtain the pure products.
8
9
1.2 equiv.
b)
MeO
OMe
Ph
Ph
OCF2H
OCF2D
F
F
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
DF2C
3a
, 17%
S
Ph
OH
(1.0 equiv.)
+
OMe
+
BF4
LiOH (2.0 equiv.)
PhF, rt, 30 min
2a
[D]-1
4
, 57%
[D]-3a
, 2%
1.2 equiv.
c)
base
XH
X
XCF2
Het
Het
Het
R
R
R
CF2
base-H
A
B
1
base or A
+
General Procedure B: phenols 2 (0.2 mmol, 1.0 equiv), NaH
(0.44 mmol, 2.2 equiv) and fluorobenzene (2.0 mL) were
added into a flame-dried Schlenk tube under argon atmosphere
and stirred at 10 oC for 30 min. Then 1 (0.24 mmol, 1.2 equiv)
was added into the mixtures in one portion directly, and the
reaction was stirred under an atmosphere of argon at 10 oC
overnight. After filtering through celite and removing the
solvent in vacuum, the residue was purified by flash column
chromatography on silica gel to obtain the pure products.
Protonation
XCF2H
Het
R
reaction mechanism in Scheme 4c. Thus, (thio)phenols are
treated with base to deliver (thio)phenoxide A, which reacts
with difluorocarbene generated in situ from reagent 1a to give
difluoromethylated anion B. Subsequent protonation yields the
desired products.
4-(difluoromethoxy)-1,1'-biphenyl
(4a)18a
.
Following
general procedure B, 4a was purified by silica gel
CONCLUSIONS
chromatography (EtOAc/PE=30/1) as a white solid (35.8 mg,
In conclusion, we have developed
difluoromethyl aryl (thio)ethers from (thio)phenols with an S-
(difluoromethyl)sulfonium salt under mild reaction
a facile access to
1
81%). H NMR (500 MHz, Chloroform-d) δ 7.60 (dd, J =
11.5, 8.0 Hz, 4H), 7.48 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.4 Hz,
1H), 7.23 (d, J = 8.3 Hz, 2H), 6.58 (t, J = 73.9 Hz, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 150.6 (t, J = 2.8 Hz),
140.1, 138.6, 128.9, 128.5, 127.5, 127.0, 119.8, 116.0 (t, J =
259.8 Hz). 19F NMR (376 MHz, Chloroform-d) δ -81.2 (d, J =
74.2 Hz).
1
conditions. In this way, (thio)phenols bearing a variety of
functional groups furnished desired products in good to
excellent yields. The mechanistic study suggests that
difluoromethylation occurs via a difluorocarbene process. A
systematic study reveals that the reactivity and
chemoselectivity of various O, S-nucleophiles toward
difluorocarbene is ArS＿ > RS＿, ArO＿ > ROH > RO＿ , ArSH,
ArOH, RSH.
1-(tert-butyl)-4-(difluoromethoxy)benzene
(4b)18a
.
Following general procedure B, 4b was purified by silica gel
1
chromatography (PE) as a colorless oil (30.2 mg, 75%). H
NMR (400 MHz, Chloroform-d) δ 7.43 – 7.38 (m, 2H), 7.11 –
7.05 (m, 2H), 6.51 (t, J = 74.3 Hz, 1H), 1.35 (s, 9H). 13C{1H}
NMR (101 MHz, CDCl3) δ 148.9 (t, J = 2.8 Hz), 148.4, 126.7,
119.1, 116.1 (t, J = 258.9 Hz), 34.4, 31.4. 19F NMR (376 MHz,
Chloroform-d) δ -79.0 (d, J = 75.7 Hz).
EXPERIMENT SECTION
General Experimental Information: 1H NMR spectra
were recorded on either a Bruker AscendTM 400MHz (400
MHz) spectrometer, or a Bruker AscendTM 500MHz (500
MHz) spectrometer at ambient temperature unless otherwise
indicated. Data were reported as follows: chemical shifts in
ppm from tetramethylsilane as an internal standard in CDCl3,
integration, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, dd = doublet-doublet, m = multiplet, br = broad),
coupling constants (Hz), and assignment. 13C NMR spectra
were recorded on either a Bruker AscendTM 500MHz (126
MHz) spectrometer or a Bruker AscendTM 400MHz (101
MHz) spectrometer at ambient temperature and were proton
decoupled. Chemical shifts are reported in ppm from
tetramethylsilane on the scale with the solvent resonance
employed as the internal standard.
1-butyl-4-(difluoromethoxy)benzene (4c). Following general
procedure B, 4c was purified by silica gel chromatography
(PE) as a colorless oil (34.3 mg, 85%). 1H NMR (400 MHz,
Chloroform-d) δ 7.20 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz,
2H), 6.50 (t, J = 74.4 Hz, 1H), 2.63 (t, J = 7.7Hz, 2H), 1.61
(dd, J = 14.9, 7.3 Hz, 2H), 1.39 (dq, J = 14.3, 7.3 Hz, 2H),
0.97 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
149.2, 140.2, 129.6, 119.4, 116.2 (t, J = 258.9 Hz), 34.9, 33.7,
22.3, 13.9. 19F NMR (376 MHz, Chloroform-d) δ -80.4 (d, J =
74.4 Hz). HRMS (ESI-TOF) m/z: (M-H)- Calcd
C11H13F2O: 199.0940. Found: 199.0931.
for
1-(difluoromethoxy)-4-phenoxybenzene (4d)18a. Following
general procedure B, 4d was purified by silica gel
chromatography (EtOAc/PE=30/1) as a colorless oil (27.0 mg,
57%). 1H NMR (500 MHz, Chloroform-d) δ 7.38 (t, J = 7.9
Hz, 2H), 7.17 – 7.11 (m, 3H), 7.08 – 7.00 (m, 4H), 6.50 (t, J =
19F NMR spectra were recorded on a Bruker AscendTM
400MHz (376 MHz) spectrometer at ambient temperature.
Chemical shifts are reported in ppm from CFCl3 as the internal
standard. ESI-MS analyses were performed in positive
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The Journal of Organic Chemistry
74.0 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 157.2,
70%). H NMR (400 MHz, Chloroform-d) δ 7.87 (d, J = 8.6
Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.66 – 7.57 (m, 1H), 7.51 (t,
J = 7.7 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.65 (t, J = 73.1 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 195.3, 154.3 (t, J =
2.7 Hz), 137.4, 134.4, 132.6, 132.2, 129.9, 128.4, 118.6, 115.4
(t, J = 261.2 Hz). 19F NMR (376 MHz, Chloroform-d) δ -81.7
(d, J = 73.3 Hz).
1
1
2
3
4
5
6
7
8
154.7, 146.5 (t, J = 2.9 Hz), 129.9, 123.5, 121.4, 117.0, 118.8,
116.03 (t, J = 260.2 Hz). 19F NMR (471 MHz, Chloroform-d)
δ -80.7 (d, J = 74.0 Hz).
2-(difluoromethoxy)-1,3-dimethoxybenzene (4e). Following
general procedure B, 4e was purified by silica gel
chromatography (EtOAc/PE=30/1) as a white solid (17.5 mg,
43%), m.p. 65.0-66.8 oC. 1H NMR (500 MHz, Chloroform-d)
δ 7.15 (t, J = 8.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 2H), 6.57 (t, J =
76.4 Hz, 1H), 3.89 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3)
δ 153.2, 129.4 (t, J = 3.5 Hz), 126.4, 116.9 (t, J = 259.5 Hz),
105.2, 56.3. 19F NMR (471 MHz, Chloroform-d) δ -81.6 (d, J
= 76.5 Hz). HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C9H11F2O3: 205.0671. Found: 205.0673.
Ethyl 4-(difluoromethoxy)benzoate (4l). Following general
procedure A, 4l was purified by silica gel chromatography
1
(EtOAc/PE=30/1) as a colorless oil (36.4 mg, 90%). H NMR
9
(400 MHz, Chloroform-d) δ 8.12 – 8.03 (m, 2H), 7.20 – 7.12
(m, 2H), 6.60 (t, J = 73.2 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H),
1.41 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
165.6, 154.6 (t, J = 2.8 Hz), 131.6, 127.4, 118.0 (t, J = 260.5
Hz), 112.8, 61.1, 14.3. 19F NMR (376 MHz, Chloroform-d) δ -
81.7 (d, J = 72.9 Hz). HRMS (ESI-TOF) m/z: (M+H)+ Calcd
for C10H11F2O3: 217.0671. Found: 217.0673.
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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
1-bromo-4-(difluoromethoxy)benzene
(4f)18a. Following
general procedure B, 4f was purified by silica gel
1
chromatography (PE) as a colorless oil (23.2 mg, 52%). H
NMR (500 MHz, Chloroform-d) δ 7.52 – 7.49 (m, 2H), 7.04
(d, J = 8.9 Hz, 2H), 6.51 (t, J = 73.4 Hz, 1H). 13C{1H} NMR
(126 MHz, CDCl3) δ 150. 0 (t, J = 2.9 Hz), 132.8, 121.5, 118.5,
115.6 (t, J = 261.2 Hz). 19F NMR (471 MHz, Chloroform-d) δ
Methyl
3-bromo-4-(difluoromethoxy)benzoate
(4m).
Following general procedure A, 4m was purified by silica gel
chromatography (EtOAc/PE=30/1) as a white solid (34.3 mg,
o
1
61%), m.p. 44.3-45.1 C. H NMR (400 MHz, Chloroform-d)
δ 8.31 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 8.6, 2.1 Hz, 1H), 7.27
(d, J = 8.6 Hz, 1H), 6.63 (t, J = 72.6 Hz, 1H), 3.94 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 151.5 (t, J = 2.8
Hz), 135.4, 130.2, 128.5, 119.9, 115.4 (t, J = 263.9 Hz), 114.8,
52.6. 19F NMR (376 MHz, Chloroform-d) δ -81.9 (d, J = 72.5
Hz). HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C9H7F2O3Br:
280.9619, 282.9599. Found: 280.9619, 282.9599.
-81.2 (d, J = 73.6 Hz).
1-(difluoromethoxy)-4-nitrobenzene (4g)
18a
. Following
general procedure A, 4g was purified by silica gel
chromatography (EtOAc/PE=30/1) as a colorless oil (25.0 mg,
1
66%). H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J = 9.2
Hz, 2H), 7.28 (d, J = 9.2 Hz, 2H), 6.66 (t, J = 72.2 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 155.5 (t, J = 2.8 Hz),
144.8, 125.8, 119.3, 115.0 (t, J = 263.7 Hz). 19F NMR (376
MHz, Chloroform-d) δ -82.6 (d, J = 72.2 Hz).
Methyl 4-(difluoromethoxy)-3-iodobenzoate (4n). Following
general procedure A, 4n was purified by silica gel
chromatography (EtOAc/PE=30/1) as a white solid (43.3 mg,
4-(difluoromethoxy)-1-methyl-2-nitrobenzene
(4h).
o
1
Following general procedure A, 4h was purified by silica gel
66%), m.p. 56.4-57.1 C. H NMR (400 MHz, Chloroform-d)
δ 8.53 (d, J = 1.4 Hz, 1H), 8.03 (dd, J = 8.5, 1.4 Hz, 1H), 7.19
(d, J = 8.5 Hz, 1H), 6.63 (t, J = 72.5 Hz, 1H), 3.94 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 164.8, 154.2 (t, J = 2.6
Hz), 141.5, 131.2, 128.6, 118.4, 115.5 (t, J = 263.8 Hz), 88.1,
52.5. 19F NMR (376 MHz, Chloroform-d) δ -81.8 (d, J = 72.4
Hz). HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C9H8F2O3I:
328.9481. Found: 328.9482.
chromatography (EtOAc/PE=30/1) as a colorless oil (28.1 mg,
1
69%). H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J = 2.5
Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.5, 2.5 Hz,
1H), 6.57 (t, J = 72.6 Hz, 1H), 2.60 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 149.3, 148.9 (t, J = 3.1 Hz), 133.9, 130.8,
124.7, 116.2, 115.3 (t, J = 263.3 Hz), 19.9. 19F NMR (376
MHz, Chloroform-d) δ -81.9 (d, J = 72.4 Hz). HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C8H8F2NO3: 204.0467. Found:
204.0468.
4-(difluoromethoxy)benzaldehyde (4o)15. Following general
procedure A, 4o was purified by silica gel chromatography
1-chloro-4-(difluoromethoxy)-2-nitrobenzene
(4i)18b
.
1
(PE) as a colorless crystal (20.3 mg, 59%). H NMR (400
Following general procedure A, 4I was purified by silica gel
MHz, Chloroform-d) δ 10.00 (s, 1H), 7.98 – 7.89 (m, 2H),
7.28 (d, J = 8.5 Hz, 2H), 6.65 (t, J = 72.8 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 190.6, 155.7 (t, J = 2.7 Hz), 133.4,
131.7, 119.2, 115.2 (t, J = 262.0 Hz). 19F NMR (376 MHz,
Chloroform-d) δ -82.0 (d, J = 72.5 Hz).
chromatography (EtOAc/PE=30/1) as a colorless oil (32.3 mg,
1
72%). H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J = 2.8
Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.8, 2.8 Hz,
1H), 6.60 (t, J = 71.9 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 149.1 (t, J = 3.0 Hz), 148.1, 133.0, 124.9, 123.8,
117.4, 115.0 (t, J = 265.3 Hz). 19F NMR (376 MHz,
Chloroform-d) δ -82.4 (d, J = 72.2 Hz).
3-(difluoromethoxy)benzaldehyde (4p). Following general
procedure A, 4p was purified by silica gel chromatography
1
(PE) as a colorless oil (15.9 mg, 46%). H NMR (400 MHz,
1-(difluoromethoxy)-4-(methylsulfonyl)benzene
(4j).
Chloroform-d) δ 10.03 (s, 1H), 7.76 (dt, J = 7.6, 1.3 Hz, 1H),
7.65 (s, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.42 (dd, J = 8.1, 2.3 Hz,
1H), 6.61 (t, J = 73.0 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 191.0, 151.6 (t, J = 2.8 Hz), 138.0, 130.6, 127.1,
125.8, 119.4, 115.5 (t, J = 261.8 Hz). 19F NMR (376 MHz,
Chloroform-d) δ -81.6 (d, J = 73.0 Hz). HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C8H7F2O2: 173.0409. Found: 173.0410.
5-bromo-2-(difluoromethoxy)benzaldehyde (4q). Following
general procedure A, 4q was purified by silica gel
Following general procedure A, 4j was purified by silica gel
chromatography (EtOAc/PE=30/1) as a white solid (20.0 mg,
o
1
45%), m.p. 81.8-83.2 C. H NMR (400 MHz, Chloroform-d)
δ 7.98 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 6.65 (t, J =
72.5 Hz, 1H), 3.07 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 154.9 (t, J = 2.8 Hz), 137.2, 129.7, 119.7, 115.1 (t, J = 263.0
Hz), 44.6. 19F NMR (376 MHz, Chloroform-d) δ -82.3 (d, J =
72.3 Hz). HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C8H9F2O3S: 223.0235. Found: 223.0237.
1
chromatography (PE) as a colorless oil (31.1 mg, 62%). H
(4-(difluoromethoxy)phenyl)(phenyl)methanone
(4k)18c
.
NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1H), 8.06 (d, J =
2.6 Hz, 1H), 7.74 (dd, J = 8.7, 2.6 Hz, 1H), 7.18 (d, J = 8.8
Hz, 1H), 6.68 (t, J = 72.2 Hz, 1H). 13C{1H} NMR (101 MHz,
Following general procedure B, 4k was purified by silica gel
chromatography (EtOAc/PE=30/1) as a colorless oil (34.8 mg,
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The Journal of Organic Chemistry
Page 6 of 9
CDCl3) δ 187.0, 151.4 (t, J = 2.9 Hz), 138.2, 131.7, 129.1,
7.54 (m, 1H), 7.42 (d, J = 8.9 Hz, 1H), 6.66 (t, J = 73.7 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 146.0 (t, J = 2.9 Hz),
132.8, 132.2, 129.2, 128.2, 128.2, 127.2, 126.6, 120.6, 116.2
(t, J = 262.6 Hz), 114.7. 19F NMR (376 MHz, Chloroform-d) δ
-80.7 (d, J = 73.7 Hz).
122.0, 119.4, 115.2 (t, J = 264.8 Hz). 19F NMR (376 MHz,
Chloroform-d) δ -81.9 (d, J = 72.2 Hz). HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C8H6F2O2Br: 250.9514, 252.9493.
Found: 250.9516, 252.9495.
1
2
3
4
5
6
7
8
N-(4-(difluoromethoxy)phenyl)acetamide (4r)15. Following
general procedure A, 4r was purified by silica gel
chromatography (EtOAc/PE=4/1) as a white solid (16.5 mg,
41%). 1H NMR (400 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.51
(d, J = 9.0 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 6.47 (t, J = 74.0
Hz, 1H), 2.18 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
168.6, 147.3 (t, J = 2.9 Hz), 135.4, 121.4, 120.4, 116.0 (t, J =
260.1 Hz), 24.4. 19F NMR (376 MHz, Chloroform-d) δ -80.7
(d, J = 73.7 Hz).
7-(difluoromethoxy)-3,4-dihydroquinolin-2(1H)-one (4x).
Following general procedure A, 4x was purified by silica gel
chromatography (EtOAc/PE=30/1) as a white solid (18.4 mg,
o
1
43%), m.p. 137.4-138.8 C. H NMR (400 MHz, Chloroform-
d) δ 9.25 (br, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.76 (dd, J = 8.2,
2.3 Hz, 1H), 6. 66 (d, J = 2.3 Hz, 1H), 6.50 (t, J = 73.9 Hz,
1H), 2.97 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 172.1, 150.5 (t, J = 2.9 Hz), 138.6,
129.0, 120.8, 115.9 (t, J = 260.1 Hz), 113.7, 107.3, 30.6, 24.7.
19F NMR (376 MHz, Chloroform-d) δ -80.8 (d, J = 73.7 Hz).
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C10H10F2NO2:
214.0674 Found: 214.0675.
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
(E)-1-(difluoromethoxy)-2-methoxy-4-(prop-1-en-1-
yl)benzene (4s). Following general procedure B, 4s was
purified by silica gel chromatography (EtOAc/PE=30/1) as a
colorless oil (26.6 mg, 62%). 1H NMR (400 MHz,
Chloroform-d) δ 7.10 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 2.0 Hz,
1H), 6.90 (dd, J = 8.2, 2.0 Hz, 1H), 6.54 (t, J = 75.4 Hz, 1H),
6.38 (dd, J = 15.7, 1.7 Hz, 1H), 6.22 (dq, J = 15.8, 6.6 Hz,
1H), 3.91 (s, 3H), 1.91 (dd, J = 6.6, 1.7 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 151.0, 138.8 (t, J = 3.1 Hz), 136.8,
130.1, 126.5, 122.3, 118.9, 116.3 (t, J = 259.4 Hz), 109.8,
55.9, 18.4. 19F NMR (376 MHz, Chloroform-d) δ -81.4 (d, J =
75.1 Hz). HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C11H13F2O2: 215.0878. Found: 215.0880.
4-(difluoromethoxy)-1H-indole (4y). Following general
procedure A, 4y was purified by silica gel chromatography
1
(EtOAc/PE=10/1) as a colorless oil (20.5 mg, 56%). H NMR
(400 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.29 (d, J = 7.7 Hz,
1H), 7.24 (t, J = 2.8 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.88
(dd, J = 6.9, 0.5 Hz, 1H), 6.70 (t, J = 2.3 Hz, 1H), 6.69 (t, J =
74.6 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 144.7 (t, J
= 2.7 Hz), 137.7, 124.4, 122.4, 120.7, 116.7 (t, J = 258.2 Hz),
109.0, 108.8, 99.6. 19F NMR (376 MHz, Chloroform-d) δ -
79.6 (d, J = 74.8 Hz). HRMS (ESI-TOF) m/z: (M+H)+ Calcd
for C9H8F2NO: 184.0568. Found: 184.0570.
2-(4-(difluoromethoxy)phenyl)ethan-1-ol (4t). Following
general procedure B, 4t was purified by silica gel
chromatography (EtOAc/PE=4/1) as a colorless oil (19.6 mg,
4-(difluoromethoxy)-2H-chromen-2-one (4z)14b. Following
general procedure B, 4z was purified by silica gel
chromatography (EtOAc/PE=30/1) as a white solid (31.4 mg,
74%). 1H NMR (400 MHz, Chloroform-d) δ 7.82 (dd, J = 7.9,
1.6 Hz, 1H), 7.67 – 7.59 (m, 1H), 7.35 (t, J = 8.4 Hz, 2H), 6.86
(t, J = 71.2 Hz, 1H), 5.99 (s, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 161.0, 159.0, 153.5, 133.4, 124.53, 123.0, 117.0,
114.5 (t, J = 264.6 Hz), 114.0, 96.4. 19F NMR (376 MHz,
Chloroform-d) δ -85.0 (d, J = 71.1 Hz).
1
52%). H NMR (400 MHz, Chloroform-d) δ 7.27 – 7.22 (m,
2H), 7.09 (d, J = 8.6 Hz, 2H), 6.51 (t, J = 74.1 Hz, 1H), 3.87
(t, J = 6.5 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H), 1.66 (br, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 149.8 (t, J = 2.8 Hz),
135.9, 130.3, 119.8, 116.0 (t, J = 259.5 Hz), 63.5, 38.4. 19F
NMR (376 MHz, Chloroform-d) δ -80.6 (d, J = 73.9 Hz).
HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C9H10F2O2Na:
211.0541. Found: 211.0542.
(difluoromethyl)(3-methoxyphenyl)sulfane
(5a)14b
.
1-(difluoromethoxy)naphthalene (4u)18a. Following general
procedure A, 4u was purified by silica gel chromatography
Following general procedure A, 5a was purified by silica gel
1
chromatography (PE) as a colorless oil (32.7 mg, 86%). H
1
(EtOAc/PE=30/1) as a colorless oil (25.3 mg, 65%). H NMR
NMR (400 MHz, Chloroform-d) δ 7.33 (t, J = 8.0 Hz, 1H),
7.19 (dt, J = 7.7, 1.3 Hz, 1H), 7.14 (t, J = 2.1 Hz, 1H), 6.99
(ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.87 (t, J = 57.0 Hz, 1H), 3.85
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.9, 130.2, 127.3,
127.2 (t, J = 3.1 Hz), 121.2 (t, J = 275.1 Hz), 120.2, 115.8,
55.4. 19F NMR (376 MHz, Chloroform-d) δ -91.2 (d, J = 57.2
Hz).
(400 MHz, Chloroform-d) δ 8.27 – 8.18 (m, 1H), 7.95 – 7.86
(m, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.63 – 7.54 (m, 2H), 7.45 (t,
J = 7.9 Hz, 1H), 7.23 (dd, J = 7.6, 0.5 Hz, 1H), 6.70 (t, J =
74.1 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 147.4 (t, J
= 2.5 Hz), 134.7, 127.8, 127.0, 126.6, 126.5, 125.4, 125.3,
121.6, 116.6 (t, J = 258.9 Hz), 113.7. 19F NMR (376 MHz,
Chloroform-d) δ -79.9 (d, J = 74.1 Hz).
(4-bromophenyl)(difluoromethyl)sulfane (5b)18a. Following
general procedure A, 5b was purified by silica gel
2-(difluoromethoxy)naphthalene (4v)18a. Following general
procedure A, 4v was purified by silica gel chromatography
1
chromatography (PE) as a colorless oil (47.5 mg, 99%). H
1
(EtOAc/PE=30/1) as a colorless oil (27.6 mg, 71%). H NMR
NMR (400 MHz, Chloroform-d) δ 7.58 – 7.53 (m, 2H), 7.49 –
7.45 (m, 2H), 6.83 (t, J = 56.6 Hz, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ 136.9, 132.6, 124.9 (t, J = 3.1 Hz), 124.8,
120.2 (t, J = 275.9 Hz). 19F NMR (376 MHz, Chloroform-d) δ
-91.6 (d, J = 56.6 Hz).
(400 MHz, Chloroform-d) δ 7.90 – 7.85 (m, 2H), 7.83 (d, J =
8.0 Hz, 1H), 7.58 – 7.48 (m, 3H), 7.32 (dd, J = 8.9, 2.4 Hz,
1H), 6.66 (t, J = 74.0 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 149.0 (t, J = 2.3 Hz), 133.8, 131.1, 130.1, 130.1,
127.8, 127.8, 127.5, 127.5, 127.0, 126.9, 125.7, 125.7, 119.7,
116.1 (t, J = 259.3 Hz), 115.4. 19F NMR (376 MHz,
Chloroform-d) δ -80.6(d, J = 73.9 Hz).
(difluoromethyl)(naphthalen-2-yl)sulfane (5c)19a. Following
general procedure A, 5c was purified by silica gel
1
chromatography (PE) as a colorless oil (37.8 mg, 90%). H
1-bromo-2-(difluoromethoxy)naphthalene (4w)15. Following
general procedure B, 4w was purified by silica gel
chromatography (EtOAc/PE=30/1) as a white solid (24.6 mg,
NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.89 (dt, J =
7.4, 3.7 Hz, 3H), 7.65 (dd, J = 8.6, 1.8 Hz, 1H), 7.63 – 7.55
(m, 2H), 6.94 (t, J = 56.9 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 135.5, 133.5, 133.4, 131.4, 129.1, 128.0, 127.8,
1
45%). H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 8.4
Hz, 1H), 7.87 (t, J = 7.7 Hz, 2H), 7.69 – 7.64 (m, 1H), 7.59 –
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127.5, 126.9, 123.3 (t, J = 3.0 Hz), 121.1 (t, J = 275.3 Hz). 19
= 4.6 Hz), 123.3 (br), 121.2 (t, J = 274.5 Hz), 111.9 (br). 19F
F
1
2
3
4
5
6
7
8
NMR (376 MHz, DMSO-d6) δ -92.1 (d, J = 55.2 Hz).
NMR (376 MHz, Chloroform-d) δ -91.1 (d, J = 56.2 Hz).
2-((difluoromethyl)thio)benzo[d]oxazole (5k)19b. Following
general procedure A, 5k was purified by silica gel
chromatography (EtOAc/PE=30/1) as a colorless oil (40.0 mg,
(difluoromethyl)(4-nitrophenyl)sulfane (5d)15. Following
general procedure A, 5d was purified by silica gel
chromatography (EtOAc/PE=30/1) as a colorless oil (25.1 mg,
1
1
99%). H NMR (400 MHz, Chloroform-d) δ 7.74 (t, J = 55.7
61%). H NMR (400 MHz, Chloroform-d) δ 8.29 – 8.22 (m,
2H), 7.78 – 7.72 (m, 2H), 6.97 (t, J = 55.8 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 148.3, 135.0 (t, J = 2.9 Hz), 134.4,
124.2, 119.6 (t, J = 276.8 Hz). 19F NMR (376 MHz,
Chloroform-d) δ -91.2 (d, J = 55.9 Hz).
Hz, 1H), 7.73 – 7.66 (m, 1H), 7.57 – 7.49 (m, 1H), 7.40 – 7.33
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.2 (t, J = 6.2
Hz), 151.7, 141.2, 125.2, 125.0, 119.8 (t, J = 276.6 Hz), 119.4,
110.4. 19F NMR (376 MHz, Chloroform-d) δ -93.2 (d, J = 55.8
Hz).
2-((difluoromethyl)thio)benzo[d]thiazole (5l)19b. Following
general procedure A, 5l was purified by silica gel
chromatography (EtOAc/PE=30/1) as a colorless oil (42.1 mg,
9
(difluoromethyl)(perchlorophenyl)sulfane (5e). Following
general procedure A, 5e was purified by silica gel
chromatography (EtOAc/PE=30/1) as a white solid (45.9 mg,
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
1
69%), m.p. 64.3-66.8 C. H NMR (400 MHz, Chloroform-d)
δ 6.93 (t, J = 57.0 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3)
δ 140.1, 136.9, 132.8, 126.3 (t, J = 3.8 Hz), 119.5 (t, J = 280.2
Hz). 19F NMR (376 MHz, Chloroform-d) δ -91.7 (d, J = 57.0
Hz). HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C7H2Cl5F2S:
330.8283, 332.8253, 334.8224. Found: 330.8282, 332.8253,
334.8223.
1
97%). H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 8.2
Hz, 1H), 7.85 (dd, J = 7.6, 0.8 Hz, 1H), 7.67 (t, J = 56.0 Hz,
1H), 7.56 – 7.47 (m, 1H), 7.47 – 7.38 (m, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 157.1 (t, J = 4.3 Hz), 152.90, 136.0,
126.7, 125.6, 122.9, 121.2, 120.3 (t, J = 277.0 Hz). 19F NMR
(376 MHz, Chloroform-d) δ -93.2 (d, J = 55.9 Hz).
N-(4-((difluoromethyl)thio)phenyl)acetamide
Following general procedure A, 5f was purified by silica gel
(5f)19a
.
General procedure for the synthesis of GRN-5299c. 4-
Difluoromethoxy-3-iodo-benzoic Acid Methyl Ester (4n):
Methyl 4-hydroxy-3-iodobenzoate 2n (1.39 g, 5.0 mmol),
LiOH (0.263 g, 2.2 equiv., 11.0 mmol) and fluorobenzene (20
mL) were added into a flame-dried Schlenk tube under argon
atmosphere and stirred at room temperature for 30 min. Then
1 (2.484g, 1.2 equiv., 6.0 mmol) was added into the mixtures
directly, and the reaction was stirred under an atmosphere of
argon at room temperature overnight. After filtering through
celite and removing the solvent in vacuum, the residue was
purified by flash column chromatography on silica gel (eluting
with ethyl acetate/hexane = 1:30) to obtain the pure product 4n
(1.135 g, 69%).
chromatography (EtOAc/PE=4/1) as a white solid (41.3 mg,
1
95%). H NMR (400 MHz, DMSO-d6) δ 10.18 (br, 1H), 7.68
(d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.38 (t, J = 56.1
Hz, 1H), 2.07 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ
169.2, 141.5, 136.6, 121.5 (t, J = 273.1 Hz), 120.1, 118.3 (t, J
= 2.7 Hz), 24.5. 19F NMR (376 MHz, DMSO-d6) δ -92.4 (d, J
= 56.2 Hz).
2-((difluoromethyl)thio)pyridine (5g)18a. Following general
procedure A, 5g was purified by silica gel chromatography
(EtOAc/PE=30/1) as a colorless oil (24.5 mg, 76%). H NMR
(400 MHz, Chloroform-d) δ 8.52 (d, J = 4.6 Hz, 1H), 7. 72 (t,
J = 56.3 Hz, 1H), 7.64 (t, J = 7.7 Hz, 2H), 7.30 (d, J = 7.7 Hz,
1H), 7.21 – 7.14 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
153.2 (t, J = 3.6 Hz), 150.1, 137.2, 124. 4 (t, J = 2.4 Hz),
121.8, 121.3 (t, J = 270.9 Hz). 19F NMR (376 MHz,
Chloroform-d) δ -96.2 (d, J = 56.4 Hz).
2-((difluoromethyl)thio)pyrimidine (5h). Following general
procedure A, 5h was purified by silica gel chromatography
(EtOAc/PE=30/1) as a colorless oil (19.2 mg, 59%). H NMR
(500 MHz, Chloroform-d) δ 8.61 (d, J = 4.9 Hz, 2H), 7.81 (t, J
= 55.9 Hz, 1H), 7.14 (t, J = 4.9 Hz, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 167.9 (t, J = 6.1 Hz), 157.8, 120.6 (t, J =
270.2 Hz), 118.3. 19F NMR (376 MHz, Chloroform-d) δ -99.6
(d, J = 55.8 Hz). HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C5H5F2N2S: 163.0136. Found: 163.0136.
1
Methyl
4-(Difluoromethoxy)-3-(pyridin-2-ylethynyl)-
benzoate (7). 2-Ethynylpyridine (6) (0.288 g, 1.01 equiv,
2.791 mmol) was charged to a solution of 4n (0.906 g, 1.00
equiv, 2.763 mmol), CuI (0.011 g, 0.020 equiv, 0.055 mmol)
and Pd(PPh3)2Cl2 (0.020 g, 0.010 equiv, 0.028 mmol) in N-
methylpyrrolidinone (NMP) (20 mL). The mixture was
degassed by evacuating and refilling via nitrogen bleed three
times, and the mixture was heated to 40 °C. Next, ammonium
hydroxide (28% solution) (1.312 g, 8 equiv) was added in one
portion, The reaction was held in this range for 6 h. After the
reaction was completed, the mixture was cooled to room
temperature, and Water (150 g, 150 mL) was added over a
period of 45 min, and the suspension was cooled to 5 °C. After
1 h at this temperature, the solids were filtered and washed
consecutively with water (60 mL), Finally, the crystals (0.807
g, 96.4% yield) were dried under vacuum. 1H NMR (400 MHz,
Chloroform-d) δ 8.62 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 8.31 (d, J
= 2.2 Hz, 1H), 8.02 (dd, J = 8.7, 2.2 Hz, 1H), 7.69 (td, J = 7.7,
1.8 Hz, 1H), 7.54 (dt, J = 7.8, 1.0 Hz, 1H), 7.29 – 7.23 (m, 2H),
6.73 (t, J = 72.8 Hz, 1H), 3.91 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 165.4, 154.7 (t, J = 2.7 Hz), 150.2, 142.7,
136.2, 135.7, 131.7, 127.5, 127.3, 123.3, 119.0, 115.6 (t, J =
263.0 Hz), 115.4, 94.2, 82.6, 52.4. 19F NMR (376 MHz,
Chloroform-d) δ -81.9 (d, J = 72.8 Hz).
1
2-((difluoromethyl)thio)thiophene (5i). Following general
procedure A, 5i was purified by silica gel chromatography
1
(PE) as a colorless oil (30.3 mg, 91%). H NMR (400 MHz,
Chloroform-d) δ 7.56 (dd, J = 5.4, 1.1 Hz, 1H), 7.39 (dd, J =
3.6, 1.0 Hz, 1H), 7.13 (dd, J = 5.4, 3.6 Hz, 1H), 6.75 (t, J =
57.1 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 138.3,
133.0, 128.3, 122.5 (t, J = 3.8 Hz), 120.4 (t, J = 277.7 Hz). 19
F
NMR (376 MHz, Chloroform-d) δ -93.5 (d, J = 57.1 Hz).
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C5H5F2S2:
166.9795. Found: 166.9796.
2-((difluoromethyl)thio)-1H-benzo[d]imidazole
(5j)19b
4-(Difluoromethoxy)-3-(pyridin-2-ylethynyl)benzoic
Acid
(8). To a mixture of 7 (0.766 g, 1.00 equiv, 2.53 mmol) in
Water (10 mL) and methanol (10 mL) at 40−45 °C was added
a solution of 50% NaOH (0.122 g, 3.04 mmol, 1.2 equiv),
keeping the temperature in the range of 40−45 °C
approximately 3 h. The reaction were diluted with 30 mL of
Following general procedure A, 5j was purified by silica gel
chromatography (EtOAc/PE=10/1) as a white solid (25.3 mg,
63%). 1H NMR (400 MHz, DMSO-d6) δ 13.13 (brs, 1H), 7.85
(t, J = 55.3 Hz, 1H), 7.59 (brs, 2H), 7.28 – 7.21 (m, 2H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 143.9 (br), 140.5 (t, J
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Page 8 of 9
* E-mail: gkliu@szu.edu.cn.
water and warmed to 45 °C. A solution of HOAc (1.0 mL) in
1
2
3
4
5
6
7
8
ORCID
water (10 mL) was slowly added over a period of 1 h. After
addition of the acetic acid solution, the mixture was cooled to
20 °C and held for one hour, and the solid was collected and
washed with water (50 mL) and dried under vacuum provide 8
as a white powder (0.700 g, 95.8% yield). 1H NMR (400 MHz,
DMSO-d6) δ 13.36 (br, 1H), 8.65 (d, J = 4.6 Hz, 1H), 8.18 (d,
J = 2.3 Hz, 1H), 8.07 (dd, J = 8.7, 1.8 Hz, 1H), 7.89 (t, J = 7.7
Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 73.0 Hz, 1H),
7.46 (t, J = 6.8 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 166.2, 154.9 (t, J = 3.2 Hz), 150.7, 142.3, 137.4, 135.2,
132.6, 128.2, 128.1, 124.4, 118.3, 116.6 (t, J = 260 Hz), 114.0,
94.4, 82.7. 19F NMR (376 MHz, DMSO-d6) δ -82.4 (d, J =
72.8 Hz).
Guo-Kai Liu: 0000-0001-7617-4267
Henry N. C. Wong: 0000-0002-3763-3085
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by the Natural Science Foun-
dation
KQJSCX20180328095508144). We thank the Instrumental
Analysis Center of Shenzhen University (Xili Campus) for
analytical work.
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of
Shenzhen
(JCYJ20170818143001461
and
(4-Difluoromethoxy-3-pyridin-2-ylethynyl-phenyl)-
(5,7-
dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone (GRN-529).
Into a flame-dried Schlenk tube was charged 8 (289 mg, 1.00
equiv, 1.0 mmol) followed by NMP (5.0 mL) and N,N-
diisopropylethylamine (DIPEA) (200 μL, 1.2 equiv, 1.2
mmol). This reaction mixture was stored at room temperature.
Into a 15 mL Schlenk tube at 25 °C was charged NMP (5.0
mL) followed by 1,1-carbonyldiimidazole (CDI) (178 mg,
1.10 equiv, 1.1 mol). This mixture was stirred to dissolve. The
solution of (8) was charged at room temperature to the
Schlenk tube over a period of 30 min and stirred at room
temperature for another 2 h to generate the activated
intermediate.
Into a 50 mL flame-dried Schlenk tube was charged NMP
(5.0 mL) followed by 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine
dihydrobromide (9) (203 mg, 1.05 equiv, 1.05 mol). To this
was charged DIPEA (302 μL, 1.83 equiv, 1.83 mmol) over a
period of 25 min and keeping the temperature below 35 °C.
The contents from the 15 mL Schlenk tube were transferred at
ambient temperature to the 50 mL Schlenk tube over a period
of 30 min. The reaction was held at ambient temperature for a
minimum of 4 h. Once the reaction was deemed complete,
water (100 mL) was added over a period of 2 h to the mixture
at 30 °C. If needed, an additional charge of water (50 mL) may
be added to aid in crystallization if crystals are not observed
after 1h. The mixture was held at 25 °C overnight and filtered.
The cake was washed with water (50 mL) and allowed to dry
on the filter overnight. The solids were weighed to provide
GRN-529 as a white powder (328 mg, 83.7% yield). 1H NMR
(400 MHz, DMSO-d6, Rotomeric mixture) δ 8.64 (d, J = 4.8
Hz, 1H), 8.47 (dd, J = 9.5, 4.9 Hz, 1H), 7.98 (s, 1H), 7.89 (t, J
= 7.6 Hz, 1H), 7.85 – 7.81 (m, 1H), 7.75 (dd, J = 27.7, 7.8 Hz,
1H), 7.67 (d, J = 7.1 Hz, 1H), 7.47 (t, J = 72.3 Hz, 1H), 7.47 –
7.40 (m, 2H), 7.35 – 7.30 (m, 1H), 4.90 (d, J = 12.8 Hz, 2H),
4.84 (d, J = 4.4 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 167.8, 157.8, 152.8, 150.7, 149.3, 142.3, 137.4, 133.8, 133.2,
131.7, 131.1, 130.5, 128.1, 124.4, 123.0, 119.0, 116.7 (t, J =
262 Hz), 114.2, 94.4, 83.1, 54.81, 52.8. 19F NMR (376 MHz,
DMSO-d6) δ -82.7 (d, J = 73.0 Hz).
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Detailed experimental procedures, characterization data,
1H, 13C, 19F NMR spectra, and HRMS (PDF)
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AUTHOR INFORMATION
Corresponding Author
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