Visible-Light-Driven Difluoromethylation of Isocyanides with S-(Difluoromethyl)diarylsulfonium Salt: Access to a Wide Variety of Difluoromethylated Phenanthridines and Isoquinolines

Article abstract of DOI:10.1021/acs.joc.0c00816

A highly efficient approach of visible-light-driven radical difluoromethylation of isocyanides to access a wide variety of difluoromethylated phenanthridines and isoquinolines is herein described. Electrophilic S-(difluoromethyl)diarylsulfonium salt proved to be a good difluoromethyl radical precursor under photoredox catalysis. A broad range of isocyanides were tolerated to furnish the corresponding difluoromethylated phenanthridines, isoquinolines, furo[3,2-c]pyridine, and pyrido[3,4-b]indole in moderate to excellent yields under mild conditions. A plausible mechanism was also proposed.

Full text of DOI:10.1021/acs.joc.0c00816

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Article
Visible-light-driven Difluoromethylation of Isocyanides with S-
(Difluoromethyl)diarylsulfonium Salt: Access to a Wide Variety
of Difluoromethylated Phenanthridines and Isoquinolines
Wen-Bing Qin, Wei Xiong, Xin Li, Jia-Yi Chen, Li-Ting Lin, Henry Nai Ching Wong, and Guo-Kai Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00816 • Publication Date (Web): 15 Jul 2020
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Page 1 of 11
The Journal of Organic Chemistry
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Visible-light-driven Difluoromethylation of Isocyanides with S-
(Difluoromethyl)diarylsulfonium Salt: Access to a Wide Variety of
Difluoromethylated Phenanthridines and Isoquinolines
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Wen-Bing Qin,a Wei-Xiong,a Xin Li,a Jia-Yi Chen,a Li-Ting Lin,a Henry N. C. Wong,b and Guo-Kai
Liu*a
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
R1
R1
Het
Het
MeO
OMe
R2
Ir(ppy)3 (3 mol%)
KOH (1.0 M, 2.0 equiv)
PEG 600 (15 uL)
R2
29 examples
HF2C
CF2H
NC
R1
N
S
+
OMe
BF4
R1
DCM, rt, argon
blue LED, ovrnight
COOR
COOR
2
R2
R2
Het
Het
6 examples
NC
N
CF2H
ABSTRACT: A highly efficient approach of visible-light-driven radical difluoromethylation of isocyanides to access a wide
variety of difluoromethylated phenanthridines and isoquinolines was herein described. Electrophilic S-
(difluoromethyl)diarylsulfonium salt proved to be a good difluoromethyl radical precursor under photoredox catalysis. Broad range
of isocyanides were tolerated to furnish the corresponding difluoromethylated phenanthridines, isoquinolines, furo[3,2-c]pyridine
and pyrido[3,4-b]indole in moderate to excellent yields under mild conditions. A plausible mechanism was also proposed.
INTRODUCTION
Scheme
1.
Visible-light
Photoredox
Radical
Difluoromethylation of Isocyanides
Previous works
a) Yu et al., Org. Lett. 2014, 16, 2938
R1
R1
fac-Ir(ppy)3
visible-light
CF
Br 2CO2Et
+
R2
R2
N
N
N
CF2H
NC
b) Hu et al., Angew. Chem. Int. Ed. 2016, 55, 2743
O
S
O
R1
S
R1
[Ru(bpy)3]Cl2 6H2O
visible-light
CF2H
+
R2
R2
N
CF2H
NC
c) Dolbier et al. Org. Lett. 2015, 17, 4401
R1
R1
fac-Ir(ppy)3
HCF
2SO2Cl
+
R2
R2
visible-light
CF2H
NC
d) This work
R1
R1
Het
Het
MeO
OMe
R2
R2
fac-Ir(ppy)3
HF2C
N
CF2H
NC
R1
S
+
OMe
BF4
visible-light
R1
COOR
COOR
2
R2
R2
Het
Het
NC
N
CF2H
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Difluoromethyl group (CF2H) is a useful structural moiety in
Page 2 of 11
Scheme 2. Substrates Scope of Difluoromethylation of
pharmaceuticals,1 agrochemicals,2 and materials,3 because of
its contribution to a profound and beneficial alternation in
chemical, physical and biological properties of the parent
compounds.4 In particular, CF2H unit plays an important role
in drug discovery and development, since it can act as a
bioisostere to CH3OH and SH units1h, 5 and serve in hydrogen-
bond donor with more lipophilicity and metabolic-stability,6
thereby benefitting the ADME (Absorption, Distribution,
Metabolism and Excretion) of drugs.[1h,4f] Therefore, the
introduction of a CF2H group into common organic molecules
represents a significant synthetic goal. Among the existing
strategies for the synthesis of difluoromethylated compounds,
the visible-light photoredox radical approach has been
emerged recently as one of the most powerful synthetic tools,
due to its numerous advantages such green, highly efficient,
mild conditions, environment-friendly and economic, etc. In
the past few years, several research groups have contributed
this research area,7 including Dolbier,8 Qing,9 and Akita10 etc.
However, most of these previous reports chose to focus on
radical difluoromethylation of alkenes. A direct radical
1
2
3
4
5
6
7
8
Isocyanidesa
R1
R1
Het
Het
Ir(ppy)3 (3 mol%)
KOH (1.0 M, 2.0 equiv)
PEG 600 (15 uL)
R2
R2
MeO
OMe
CF2H
NC
R1
N
HF2C
S
1
3
+
DCM, rt, argon
blue LED, ovrnight
OMe
BF4
R1
COOR
COOR
2
R2
R2
Het
Het
NC
N
CF2H
3
9
1
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60
b
R
3aa
3ab
3ac
3ad
3ae
3ah
, R = H, 77% (61%)
, R = Cl, 70%
, R = Br, 52%
, R = CF3, 53%
3ai
3aj
, R = Me, 70%
CF2H
MeO
, R = tBu, 72%
, R = OMe, 73%
, R = SMe, 65%
, R = Ph, 60%
CF2H
N
3ak
, R = NO2, 18%
, R = CN, 48%
N
3al
3am
3af
3ag
, R = CONMe2, 61%
, R = SO2Me, 69%
3an
, R = F, 70%
3ao
, 36%
OMe
OMe
CF2H
MeO
MeO
OMe
CF2H
CF2H
N
N
N
difluoromethylation
of
isocyanides
to
install
3ap
3ap'
3aq
, 39%
, 40%
, 47%
difluoromethylated phenanthridines and isoquinolines is still
underdeveloped. More importantly, both phenanthridines and
isoquinolines are very useful skeletons which frequently occur
in natural products and biologically active molecules.11
Consequently, the facile synthesis of difluoromethylated
phenanthridines and isoquinolines from the corresponding
isocyanides via a radical pathway has attracted considerable
attention in the past few years. The current methods to access
difluoromethylated phenanthridines and isoquinolines mainly
involve transition-metal catalysis12 or metal-free conditions.13
However, very few visible-light-driven protocols have been
3ba
, R = Me, 79%
CF2H 3bb, R = OMe, 75%
CF2H
CF2H
N
N
3bc
3bd
3be
, R = F, 75%
, R = Cl, 68%
, R = CF3, 55%
, R = NO2, 32%
N
N
N
3bf
3bg
, R = CO2Et, 62%
3ca
3cb
, 78%
, 53%
R
CO2Me
N
CO2Me
N
Ph
S
CF2H
CF2H
S
CF2H
N
N
CF2H
3cc
3cd,
49%
, 49%
3da
3db
, 63%
, 44%
F
Br
CO2Me
N
CO2Me
CO2Me
N
CO2Me
Table 1. Survey of the Reaction Conditionsa
N
N
MeO
OMe
CF2H
CF2H
CF2H
N
O
PC
(3.0 mol%)
CF2H
CF2H
HF2C
base (2.0 equiv)
S
+
F
Br
NC
OMe
N
solvent, rt, argon
blue LED, overnight
BF4
3dc
3dd
3df
, 42%
, 51%
, 41%
3de, 34%
a
Reaction conditions (unless otherwise specified): 1 (0.1 mmol), 2 (0.2
1aa
2
3aa
mmol), Ir(ppy)3 (3 mol%), PEG 600 (15 μL) and KOH (1M, 2.0 equiv) in
DCM (2 mL) were irradiated with a 12 W blue LED at room temperature under
argon atmosphere overnight, isolated yields. b This reaction was performed in
3.0 mmol scale of 1aa to give 61% isolated yield of 3aa.
yield
(%)
entry
[PC]
base/(equiv)
solvent
1
Ir(ppy)3
--
DCM
DCM
DCM
DCM
DCM
1,4-doxane
THF
37
ND
ND
26
ND
30
31
19
4
recorded. Yu and co-worker disclosed the first visible-light-
driven approach for radical difluoromethylation of isocyanides
using BrCF2CO2Et as the difluoromethyl radical regent
(Scheme 1a).14 Subsequently, Hu15 and Dolbier16 employed
difluoromethylsulfone (Scheme 1b) and HCF2SO2Cl (Scheme
1c) to realize the same goal under visible-light photoredox
catalysis, respectively. Although the aforementioned progress
has been rather useful,
difluoromethylation of isocyanides is still lacking. Very
recently, we developed the bench-stable S-
(difluoromethyl)diarylsulfonium salts 2 as a highly efficient
electrophilic difluoromethylating reagent and difluorocarbene
precursor.17 As a part of our continuous effort for the synthesis
of biologically active fluorinated compounds, herein we
disclose a facile visible-light-driven photoredox process for
radical difluoromethylation of isocyanides to assemble 6-
2
--
Ru(bpy)2Cl2
Eosin Y
4CzPN
3
--
4
5b
--
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
--
6
--
7
--
8
--
MeCN
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
a facile and practical direct
9
Et3N (2.0 equiv)
10
11
12
13
14
15
16
17c
(iPr)2NEt (2.0 equiv)
DBU (2.0 equiv)
8
26
71
58
34
46
18
79
KOH (1M, 2.0 equiv)
NaOH (1M, 2.0 equiv)
K2HPO4 (1M, 2.0 equiv)
KOAc (1M, 2.0 equiv)
KOH (2.0 equiv)
KOH (1M, 2.0 equiv)
a
difluoromethyl phenanthridine derivatives with
difluoromethyl radical reagent.
2 as a
Reaction conditions (unless otherwise specified): 1a (0.1 mmol),
photocatalyst (3.0 mol%), solvent and 2 (0.2 mmol) was added in a tube,
the reaction were irradiated with a 12 W blue LED at room temperature
b
c
under argon atmosphere overnight, isolated yield. Without blue LED.
PEG 600 (15 μL) was added. Eosin Y = 2,4,5,7-Tetrabromofluorescein
disodium salt, 4CzPN 3,4,5,6-tetrakis(carbazol-9-yl)-1,2-
dicyanobenzene
RESULTS AND DISCUSSION
=
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The Journal of Organic Chemistry
We initially used isocyanide 1a as a model substrate to efficient method for the synthesis of a variety of important
1
2
3
4
5
6
7
8
optimize the reaction conditions (Table 1). Reagent 2 was
employed to generate the difluoromethyl radical by blue light
difluoromethylated heterocyclic compounds which possess
high potentials in pharmaceuticals and drug discovery.
Ir(ppy) (3 mol%)
irritation under
in DCM. To our delight, the
3
To demonstrate the practicability of this radical
difluoromethylation method, the synthesis for the drug 6-
difluoromethyltrispheridine, which is a DNA intercalator18,
was exploited. As shown in scheme 3, the dioxole derivative
1ar could smoothly undergo reaction in a regioselectively
manner to afford 6-difluoromethylated trispheridine 3ar as a
single isomer in 71% yield under the standard conditions ,
while no 3ar’ was found, thus clearly suggesting its
practicability and potential in medical chemistry and drug
discovery.
desired difluoromethylphenanthridine (3a) was formed in an
isolated yield of 37% (entry 1). Although the reagent’s
byproduct trimethoxyphenyl sulfide is also a very electron-
rich arene, which might be a good radical acceptor, no
corresponding difluoromethylation side product was found.
Probably isocyanide is more active acceptor toward
difluoromethyl radical than trimethoxyphenyl sulfide in this
9
10
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Other
Ru(bpy) Cl
,
2 2
reaction.
Eosin Y and
photoredox catalysts such as
4CzPN were next tested, but no desired products
were found (entries 2-3) except 4CzPN in 26% yield (entry 4).
It should be noted that the reaction does not proceed in the
absence of blue LED (entry 5). Using other solvents did not
give better results (entries 6-8). In order to improve the
reaction efficiency, bases were added to neutralize the acid
generated during the reaction course (entries 9-17). It was
found that organic bases were ineffective (entries 9-11), and
difluoromethylating reagent 2 might be decomposed under
(iPr) NEt, thus resulting in decreasing yields
9-10). Gratifyingly, we found that aqueous basic solution
would promote the reaction (entries 12-15). Thus, aqueous
KOH (1M) dramatically increased the yield to 71% (entry 12),
while only 18% yield of product was afforded when insoluble
KOH powder was used (entry 16). The yields were further
slightly improved to 79% when 15 μL of PEG 600 was
employed as an additive (entry 17), probably benefiting from
its acting as a co-solvent to enhance miscibility of KOH
aqueous solution and organic solvent dichloromethane.
Scheme 3. Synthesis of Difluoromethylated Trispheridine
O
O
O
Ir(ppy)3 (3 mol%)
KOH (1.0 M, 2.0 equiv)
PEG 600 (15 uL)
O
O
O
CF2H
CF2H
2
(2.0 equiv)
C
N
N
N
DCM, rt, argon
blue LED, overnight
1ar
3ar
3ar'
, 71%
, 0%
Trispheridine derivative
Et3N or
(entries
2
To gain detailed insight into the mechanism, the cyclic
voltammogram experiment was carried out. As shown in
Scheme 4, the measured reduction potential of S-
red
(difluoromethyl)diarylsulfonium salt 2 is Ep = -1.34 V vs.
SCE in CH3CN, thus inferring that reagent 2 could be readily
reduced by the selected photoexcited complex [Ir(ppy)3*]
(E1/2red[IrIV/Ir*III] = -1.73 V vs. SCE)19.
Based on our experimental results and previous mechanistic
studies16, a plausible mechanism is proposed (Scheme 5).
Initially, the excited [Ir(ppy)3*] catalyst reduces the
With the optimized reaction conditions in hand (entry 17,
Table 1), we then examined the substrate scope of this process
under optimized reaction conditions (Scheme 2). These
substrates with both electron-donating (1ab-1af, 1ap, 1ba-
1bb) and electron-withdrawing (1ag-1aj, 1al-1an, 1bc-1bg)
substituents, regardless of para- or meta-positions on the
biphenyl moieties of the isocyanides, were compatible to this
reaction, leading to the formation of the corresponding
products in moderate to good yields, although substrates
bearing strongly electron-withdrawing groups (1ak, 1bf) gave
poor yields. A 3.0 mmol scale conversion was performed and
419.3 mg 3aa was isolated (61% yield), revealing the potential
application of this method.
Scheme 4. Cyclic Voltammetry Study of Reagent 2
However, the ortho-OMe substituent and multiple OMe
substituents in the benzene ring decreased reactivity to afford
lower yields (3ao, 3aq), probably due to their steric hindrance.
The 3-methoxy-substituted isocyanide 1ap gave two
corresponding products 3ap and 3ap' in yields of 40% and
47%, respectively. Importantly, Substrates containing
heteroaryl moieties including indole, pyrrole and
thianaphthene were also suitable substrates for this
transformation, providing their corresponding products 3ca-
3cd in moderate to good yields.
Scheme 5. Proposed Mechanism
Remarkably, 2-isocyanoacrylates could also react smoothly
with the difluoromethyl radical reagent, offering the desired
difluoromethylated isoquinolines (3da-3dd), furo[3,2-
c]pyridine (3de) and pyrido[3,4-b]indole (3df) in moderate
yields. It is worth noting that direct radical
difluoromethylation in a regioselective manner of the parent
heterocycles remain still a highly challenge task so far, thus
suggesting that this protocol indeed provides a practical and
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Page 4 of 11
positive ionization mode on an Agilent 1260-Infinity LC/MSD.
OMe
Ph
1
2
3
4
5
6
7
8
All high resolution mass spectra were obtained on a Thermo
Scientific Q-Exactive (HR/AM) OrbitrapTM mass spectrometer.
Commercially available reagents were used as received.
Reactions were monitored by TLC. Flash chromatography:
silica gel (300-400 mesh).
S
BF4
CF2H
OMe
MeO
Ir*III
hv
SET
Photoredox
catalytic
cycle
R1
R2
R1
R2
H
N
IrIV
CF2H
CF2H
IrIII
General Procedure for the Preparation of Isocyanides.
-H
CF2H
N
All known isocyanides were prepared according to a
reported method, and analytical data are in agreement with
those reported in the literature. 14, 15, 20
SET
R1
R2
C
3
C
9
N
R1
R1
H
N
CF2H
CF2H
10
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12
13
14
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60
General Procedure for synthesis of 2-(isocyano)-1,1 ’ -
biaryl derivatives A:
N
1
R2
R2
Step 1
PdCl2(PPh3)2 (2 mol%)
K2CO3 (5.0 equiv)
NH2
A
B
I
B(OH)2
+
Het
Het
S-(difluoromethyl)diarylsulfonium salt 2 to generate the CF2H
radical, followed by an intermolecular addition to the
isocyanide functionality of 1 to form imidoyl radical A.
Radical A subsequently undergoes an intramolecular attack
onto the pendant aromatic ring to give cyclohexadienyl-type
radical B. Then radical B is oxidized by the high-valent
catalyst IrIV (E1/2ox[IrIV/IrIII] = +0.77 V vs. SCE)19 through a
single electron transfer (SET) process to afford the
cyclohexadienyl cation C along with the regeneration of
catalyst. Finally, aromatization of C via deprotonation leads to
the desired product 3. Another possible pathway is
deprotonation of radical B, followed by oxidation with IrIV to
give final desired product 3.
DME, 80 o
over night
C
NH2
S1
S2
Step 1: 2-Iodoarylamine S1 (1 mmol, 1.0 equiv),
Arylboronic acid (1.2 mmol, 1.2 equiv) and an aqueous
solution of K2CO3 (2 M, 2.5 mL) were placed in a dry three
necked flask under Ar. Then, DME (10 mL) was added and
the mixture was stirred for 30 min at room temperature under
Ar. To the stirred mixture, PdCl2(PPh3)2 (0.02 mmol, 0.02
equiv) was added at room temperature and the mixture was
stirred at 80 ℃ (oil bath) over night. The mixture was then
cooled to room temperature and diluted with EtOAc. The
organic layer was washed with water and dried over
anhydrous MgSO4. The solvent was removed under reduced
pressure and the residue was purified by flash column
chromatography on silica gel by using a 30:1 mixture of
hexane/EtOAc as an eluent to provide S2.
CONCLUSIONS
In conclusion, we have developed an effective and practical
approach for the assembling of
difluoromethylated phenanthridines, isoquinolines, furo[3,2-
c]-pyridine and pyrido[3,4-b]indole from isocyanides with S-
(difluoromethyl)diarylsulfonium salt 2 via visible-light-driven
radical difluoromethylation process under mild reaction
a wide variety of
Step 2
HCOOH
Ac2O
Step 3
POCl3
Et3N
NHCHO
NH2
NC
Het
Het
Het
THF, 0 o
2 h
C
THF, 0 o
2 h
C
S3
S2
Step 2: Acetic formic anhydride, which was prepared from
the reaction of acetic anhydride (0.34 mL) with formic acid
(0.76 mL) at 55 ℃ (oil bath) for 2 h, was added dropwise to a
stirred solution of S2 at 0 ℃ in THF (6 mL) and the mixture
was stirred for 2 h at room temperature. Volatiles were
removed in vacuum to afford S3 as white solid. This material
was used for the subsequent dehydration without further
purification.
conditions. This transformation tolerated
a variety of
functional groups to furnish desired products in moderate to
excellent yields. We believe that this protocol would provide a
facile method to access many pharmaceutically important
difluoromethylated heterocyclic compounds, and is of interest
to organic chemists and medicinal chemists.
EXPERIMENT SECTION
Step 3: A THF solution (6 mL) of the whole amount of S3
and Et3N (1 mL, 7 mmol) was cooled to 0 ℃. Then, POCl3
(0.3 mL, 3 mmol) was added drop wise and the mixture was
stirred at 0 ℃ for 2 h. After the reaction was completed, the
mixture was quenched by aqueous saturated Na2CO3 solution
and stirred for 1 h. The mixture was extracted with CHCl3
three times. The combined organic layer was dried over
anhydrous MgSO4. The solvent was removed under reduced
pressure and the crude product was purified by flash column
chromatography on silica gel by using a 20:1 mixture of
hexane/EtOAc as an eluent to provide analytical pure product
Isocyanides.
General Experimental Information: 1H NMR spectra
were recorded on a Bruker AscendTM 400MHz (400 MHz) or
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 a Bruker AscendTM 400MHz (101 MHz), Bruker
AscendTM 500MHz (126 MHz) or Bruker AscendTM 600MHz
(151 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. 19F NMR spectra were
recorded on a Bruker AscendTM 400MHz (376 MHz)，Bruker
AscendTM 500MHz (471 MHz) spectrometer at ambient
temperature. Chemical shifts are reported in ppm from CFCl3
as the internal standard. ESI-MS analyses were performed in
General Procedure for synthesis of 2-(isocyano)acrylates
B:
CO2Et
CO2Et
Step 1
NaH
(1.2 equiv)
Step 2
POCl3
Et3N
R
O
R
R
NC
NHCHO
CO2Et
+
THF, 0 o
2 h
C
THF, rt.
2 h
Het
NC
Het
Het
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The Journal of Organic Chemistry
Step 1: A mixture of Arylaldehyde or Arylketone (S4, 5.0
In a 15 mL flame-dried Schlenk tube (Synthware Glass,
Beijing F580810) was charged with isocyanide 1 (0.1 mmol,
1.0 equiv), diarylsulfonium salt 2 (0.2 mmol, 2.0 equiv), fac-
Ir(ppy)3 (0.003 mmol, 0.03 equiv), PEG 600 (15 µL). The
flask was evacuated and backfilled with argon for 3 times.
KOH (1.0 M, 200 µL, 2.0 equiv) and CH2Cl2 (2.0 mL) was
added with syringe under argon. The mixture was then
irradiated by a 12W blue LED (450 nm) strip overnight (laid
0.5 CM away from the Schlenk tube). The mixture was poured
into a separatory funnel containing 10 mL H2O and 10 mL
CH2Cl2. The layers were separated and the aqueous layer was
extracted with CH2Cl2 (2×10 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure after filtration. The residue was purified by flash
chromatography on silica gel to afford the desired product
difluoromethylated phenanthridines and isoquinolines 3.
1
2
3
4
5
6
7
8
mmol) and methyl isocyanoacetate (5.0 mmol) in THF (10 ml)
was added dropwise to a suspension of NaH (60% in oil) (0.24
g, 6.0 mmol) in THF (10.0 ml) at room temperature. After
stirring for 2 h at room temperature, 10% AcOH was added to
the mixture at 0 °C until there is no hydrogen release. The
solvent was removed under reduced pressure and the residue
was extracted with CH2Cl2 three times and the extract was
washed with H2O, dried over Na2SO4 and concentrated under
reduced pressure. Further recrystallization in MeOH afforded
the product S5 as a white solid.
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60
Step 2: THF (10.0 mL), NEt3 (2.8 mL, 20 mmol) and S5
(5.0 mmol) were added to an oven-dried three necked flask
under N2 atmosphere and cooled to 0 °C. POCl3 (0.47 mL, 5.0
mmol) was added dropwise and the mixture was stirred for 2 h
at 0 °C after the addition was completed. Then the mixture
was quenched by sat. Na2CO3 and stirred for another 1 h. The
mixture was extracted with CH2Cl2 three times, dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel
(hexane/EtOAc = 20/1) to give analytical pure product 1da-df.
3.0
mmol
scale
Procedure
for
Radical
Difluoromethylation of Isocyanides
In a 100 mL flame-dried Schlenk tube (Synthware Glass,
Beijing F588100N) was charged with isocyanide 1aa (3.0
mmol, 1.0 equiv), diarylsulfonium salt 2 (6.0 mmol, 2.0
equiv), fac-Ir(ppy)3 (0.09 mmol, 0.03 equiv), PEG 600 (450
µL). The flask was evacuated and backfilled with argon for 3
times. KOH (1.0 M, 6.0 mL, 2.0 equiv) and CH2Cl2 (60 mL)
was added with syringe under argon. The mixture was then
irradiated by a 12W blue LED (450 nm) strip overnight (laid
0.5 CM away from the Schlenk tube). The mixture was poured
into a separatory funnel containing 60 mL H2O and 30 mL
CH2Cl2. The layers were separated and the aqueous layer was
extracted with CH2Cl2 (2×30 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure after filtration. The residue was purified by flash
chromatography on silica gel to afford the desired product 6-
(difluoromethyl)phenanthridine (3aa) as a white solid (419.3
mg, 61%).
2-isocyano-3',4',5'-trimethoxy-1,1'-biphenyl
Following general procedure A, 1aq was purified by silica gel
(1aq).
chromatography (PE/EtOAc =20/1) as a white solid (142.7
1
mg, 53%). Mp: 88.5-90.0 °C; H NMR (400 MHz, CDCl3) δ
7.56 – 7.43 (m, 3H), 7.42 – 7.34 (m, 1H), 6.75 (s, 2H), 3.93 (s,
9H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.8, 153.2, 138.8,
138.3, 132.4, 130.4, 129.5, 128.1, 128.0, 124.5, 106.4, 61.0,
56.3. HRMS (ESI) m/z [M+H]+ calculated for C16H16NO3
270.1125; found 270.1123.
Methyl 2-isocyano-[1,1'-biphenyl]-4-carboxylate (1bg).
Following general procedure A, 1bg was purified by silica gel
chromatography (PE/EtOAc =5/1) as a white solid (165.8 mg,
1
66%). Mp: 57.1-58.3 °C; H NMR (400 MHz, CDCl3) δ 8.18
(d, J = 1.5 Hz, 1H), 8.14 (dd, J = 8.1, 1.7 Hz, 1H), 7.57 – 7.47
(m, 6H), 4.45 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 167.79, 164.7, 142.8,
136.1, 130.8, 130.6, 130.4, 129.0, 128.9, 128.8, 128.7, 124.7,
61.7, 14.3. HRMS (ESI) m/z [M+H]+ calculated for
C16H14NO2 252.1020; found 252.1019.
6-(difluoromethyl)phenanthridine
(3aa).15
Following
general procedure, 3aa was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (17.7 mg,
77%). 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J = 8.3 Hz, 1H),
8.59 (d, J = 7.8 Hz, 2H), 8.22 (d, J = 7.7 Hz, 1H), 7.90 (t, J =
7.6 Hz, 1H), 7.83 – 7.72 (m, 3H), 7.05 (t, J = 54.4 Hz, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 151. 34 (t, J = 26.4 Hz),
142.4, 133.8, 131.2, 130.6, 129.1, 128.7, 127.8, 126.5 (t, J =
4.1 Hz), 125.0, 122.4, 122.2, 118.5 (t, J = 243.4 Hz). 19F NMR
(471 MHz, CDCl3) δ -111.1 (d, J = 54.2 Hz).
Methyl
(Z)-3-(furan-2-yl)-2-isocyanoacrylate
(1de).
Following general procedure B, 1de was purified by silica gel
chromatography (PE/EtOAc =20/1) as a white solid (310.4
1
mg, 35%). Mp: 70.8-72.0 °C; H NMR (400 MHz, CDCl3) δ
7.70 (d, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.35 (d, J = 3.7 Hz, 1H),
6.67 (dd, J = 3.7, 1.8 Hz, 1H), 3.93 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 173.9, 161.7, 147.9, 146.7, 126.1, 119.6,
113.5, 110.8, 53.4. HRMS (ESI) m/z [M+H]+ calculated for
C9H8NO3 178.0499; found 178.0495.
6-(difluoromethyl)-8-methylphenanthridine
(3ab).15
Following general procedure, 3ab was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (17.0 mg,
1
70%). H NMR (500 MHz, CDCl3) δ 8.49 – 8.44 (m, 2H),
8.25 (s, 1H), 8.16 – 8.05 (m, 1H), 7.69 – 7.61 (m, 3H), 6.95 (t,
J = 54.4 Hz, 1H), 2.53 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 151.0 (t, J = 26.4 Hz), 142.0, 137.9, 133.1, 131.7,
130.4, 128.6, 128.6, 125.7 (t, J = 4.1 Hz), 125.1, 122.6, 122.3,
122.0, 118.3 (t, J = 243.4 Hz), 21.9. 19F NMR (471 MHz,
CDCl3) δ -111.3 (d, J = 54.5 Hz).
Methyl (Z)-2-isocyano-3-(1-methyl-1H-indol-3-yl)acrylate
(1df). Following general procedure B, 1df was purified by
silica gel chromatography (PE/EtOAc =5/1) as a white solid
1
(564.6 mg, 47%). Mp: 154.1-155.0 °C; H NMR (400 MHz,
CDCl3) δ 8.81 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H),
7.41 – 7.31 (m, 3H), 3.93 (s, 3H), 3.90 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 163.8, 162.8, 137.8, 136.7, 135.7, 129.1,
123.4, 122.0, 117.9, 110.2, 108.5, 107.7, 52.5, 33.8. HRMS
(ESI) m/z [M+H]+ calculated for C14H13N2O2 241.0972; found
241.0970.
8-(tert-butyl)-6-(difluoromethyl)phenanthridine
(3ac).15
Following general procedure, 3ac was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (20.6 mg,
72%). 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J = 8.8 Hz, 1H),
8.60 – 8.55 (m, 2H), 8.21 (dd, J = 6.9, 2.5 Hz, 1H), 8.00 (dd, J
= 8.8, 1.9 Hz, 1H), 7.75 (tt, J = 7.1, 5.2 Hz, 2H), 7.07 (t, J =
54.4 Hz, 1H), 1.50 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3)
General Procedure for Radical Difluoromethylation of
Isocyanides
ACS Paragon Plus Environment

The Journal of Organic Chemistry
δ 151.4 (t, J = 26.3 Hz), 150.9, 142.2, 131.7, 130.4, 129.7, 8-bromo-6-(difluoromethyl)phenanthridine
Page 6 of 11
(3ai).15
1
2
3
4
5
6
7
8
128.7, 128.5, 125.0, 122.5 (t, J = 1.8 Hz), 122.2, 122.0, 121.9
(t, J = 4.4 Hz), 118.5 (t, J = 243.5 Hz), 35.2, 31.2. 19F NMR
(471 MHz, CDCl3) δ -111.3 (d, J = 54.3 Hz).
Following general procedure, 3ai was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (16.1 mg,
52%). 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J = 1.8 Hz, 1H),
8.53 – 8.50 (m, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.18 (dd, J = 8.1,
1.1 Hz, 1H), 7.96 (dd, J = 8.9, 2.0 Hz, 1H), 7.80 (td, J = 8.2,
7.6, 1.5 Hz, 1H), 7.76 (td, J = 7.8, 7.3, 1.4 Hz, 1H), 6.99 (t, J =
54.3 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 150.2 (t, J
= 26.8 Hz), 142.3, 134.4, 132.4, 130.7, 129.4, 129.1, 128.8 (t,
J = 4.7 Hz), 124.3, 124.1, 123.4 (t, J = 1.8 Hz), 122.0, 121.9,
118.1 (t, J = 243.6 Hz). 19F NMR (471 MHz, CDCl3) δ -111.0
(d, J = 54.6 Hz).
6-(difluoromethyl)-8-methoxyphenanthridine
(3ad).14,15
Following general procedure, 3ad was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (19.0 mg,
73%). 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J = 9.1 Hz, 1H),
8.44 – 8.37 (m, 1H), 8.13 – 8.04 (m, 1H), 7.81 (d, J = 2.1 Hz,
1H), 7.66 – 7.59 (m, 2H), 7.43 (dd, J = 9.1, 2.6 Hz, 1H), 6.95
(t, J = 54.4 Hz, 1H), 3.92 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 158.8, 150. 3 (t, J = 26.6 Hz), 141.6, 130.4, 128.7,
128.3, 128.1, 125.1, 124.0, 123.7 (d, J = 2.1 Hz), 122.5, 121.7,
118.6 (t, J = 243.3 Hz), 105. 9 (t, J = 4.6 Hz), 55.6. 19F NMR
(471 MHz, CDCl3) δ -111.9 (d, J = 54.3 Hz).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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34
35
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56
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60
6-(difluoromethyl)-8-(trifluoromethyl)phenanthridine
(3aj).15 Following general procedure, 3aj was purified by silica
gel chromatography (PE/EA = 10/1) as a white solid (15.8 mg,
53%). 1H NMR (500 MHz, CDCl3) δ 8.87 (s, 1H), 8.79 (d, J =
8.7 Hz, 1H), 8.62 (d, J = 8.1 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H),
8.11 (d, J = 8.7 Hz, 1H), 7.88 (t, J = 7.5 Hz, 1H), 7.83 (t, J =
7.6 Hz, 1H), 7.06 (t, J = 54.2 Hz, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 151.2 (t, J = 26.9 Hz), 143.0, 135.9, 130.8,
130.3, 129.7 (q, J = 33.0 Hz), 129.3, 127.1 (q, J = 3.1 Hz),
124.0 (q, J = 4.0 Hz), 124.0, 123.8 (q, J = 272.6 Hz), 123.5,
122.5, 121.6 (t, J = 1.7 Hz), 118.1 (t, J = 243.6 Hz). 19F NMR
(471 MHz, CDCl3) δ -62.9, -110.4 (d, J = 54.1 Hz).
6-(difluoromethyl)-8-(methylthio)phenanthridine
(3ae).15
Following general procedure, 3ae was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (17.9 mg,
1
65%). H NMR (500 MHz, CDCl3) δ8.56 (d, J = 8.7 Hz, 1H),
8.55 – 8.52 (m, 1H), 8.34 – 8.31 (m, 1H), 8.22 – 8.18 (m, 1H),
7.80 – 7.74 (m, 3H), 7.04 (t, J = 54.4 Hz, 1H), 2.67 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 150.1 (t, J = 26.7 Hz),
141.5, 139.6, 131.1, 130.3, 130.2, 128.9, 128.9, 124.9, 122.8,
122.6, 121.9, 121.4 (t, J = 4.6 Hz), 118.0 (t, J = 243.6 Hz),
15.4. 19F NMR (471 MHz, CDCl3) δ -110.8 (d, J = 54.4 Hz).
6-(difluoromethyl)-8-nitrophenanthridine (3ak).15 Following
general procedure, 3ak was purified by silica gel
chromatography (PE/EA = 10/1) as a white solid (5.0 mg,
6-(difluoromethyl)-8-phenylphenanthridine
(3af).14,15
Following general procedure, 3af was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (18.4 mg,
60%). 1H NMR (500 MHz, CDCl3) δ 8.75 (d, J = 1.8 Hz, 1H),
8.67 (d, J = 8.6 Hz, 1H), 8.55 (dd, J = 7.6, 1.7 Hz, 1H), 8.19
(dd, J = 7.9, 1.4 Hz, 1H), 8.10 (dd, J = 8.6, 1.8 Hz, 1H), 7.78 –
7.70 (m, 4H), 7.52 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H),
7.05 (t, J = 54.4 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ
151.4 (t, J = 26.5 Hz), 142.4, 140.6, 140.0, 132.8, 130.6, 130.5,
129.1, 129.0, 128.7, 128.1, 127.5, 124.8, 124.3 (t, J = 4.3 Hz),
123.0, 122.8, 122.2, 118.5 (t, J = 243.4 Hz). 19F NMR (471
MHz, CDCl3) δ -111.0 (d, J = 54.5 Hz).
1
18%). H NMR (500 MHz, CDCl3) δ 9.54 – 9.44 (m, 1H),
8.85 (d, J = 9.1 Hz, 1H), 8.70 (dd, J = 9.1, 2.3 Hz, 1H), 8.67 (d,
J = 8.1 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.94 (td, J = 8.1, 1.3
Hz, 1H), 7.88 (td, J = 8.2, 1.2 Hz, 1H), 7.05 (t, J = 54.1 Hz,
1H). 19F NMR (471 MHz, CDCl3) δ -110.2 (d, J = 54.4 Hz).
6-(difluoromethyl)phenanthridine-8-carbonitrile
(3al).
Following general procedure, 3al was purified by silica gel
chromatography (PE/EA = 10/1) as a white solid (12.2 mg,
48%). 1H NMR (500 MHz, CDCl3) δ 8.95 (s, 1H), 8.79 (d, J =
8.6 Hz, 1H), 8.63 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H),
8.10 (d, J = 8.6 Hz, 1H), 7.93 (t, J = 7.5 Hz, 1H), 7.87 (t, J =
7.6 Hz, 1H), 7.03 (t, J = 54.1 Hz, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 150.7 (t, J = 27.4 Hz), 143.3, 136.2, 132.4,
132.0 (t, J = 4.8 Hz), 131.0, 130.9, 129.6, 123.8, 123.7, 122.7,
121.7, 118.0 (t, J = 243.6 Hz), 111.5. 19F NMR (376 MHz,
CDCl3) δ -109.6 (d, J = 54.3 Hz). HRMS (ESI) m/z [M+H]+
calculated for C15H9 F2N2 255.0729; found 255.0722.
6-(difluoromethyl)-8-fluorophenanthridine
(3ag).15
Following general procedure, 3ag was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (17.3 mg,
70%). 1H NMR (500 MHz, CDCl3) δ 8.64 (dd, J = 9.1, 5.2 Hz,
1H), 8.50 (dd, J = 6.8, 2.7 Hz, 1H), 8.23 – 8.17 (m, 2H), 7.80
– 7.73 (m, 2H), 7.64 (ddd, J = 9.1, 8.1, 2.6 Hz, 1H), 7.00 (t, J
= 54.3 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 161.4 (d,
J = 249.3 Hz), 150.5 (dt, J = 27.1, 4.2 Hz), 142.1 (d, J = 1.3
Hz), 130.7, 130.5, 129.1, 129.0, 124.9 (d, J = 8.6 Hz), 124.53,
123.4 (dt, J = 8.8, 1.7 Hz), 121.9, 120.6 (d, J = 24.1 Hz), 118.2
(t, J = 243.4 Hz), 111.2 (dt, J = 22.7, 4.5 Hz). 19F NMR (471
MHz, CDCl3) δ -111.1 (m, 1F), -111.5 (d, J = 53.4 Hz, 2F).
6-(difluoromethyl)-N,N-dimethylphenanthridine-8-
carboxamide (3am).15 Following general procedure, 3am was
purified by silica gel chromatography (PE/EA = 4/1) as a
1
white solid (18.4 mg, 61%). H NMR (500 MHz, CDCl3) δ
8.72 (d, J = 8.6 Hz, 1H), 8.63 – 8.61 (m, 1H), 8.59 (dd, J = 8.0,
1.4 Hz, 1H), 8.21 (dd, J = 8.0, 1.3 Hz, 1H), 8.01 (dd, J = 8.5,
1.6 Hz, 1H), 7.82 (td, J = 8.1, 7.6, 1.6 Hz, 1H), 7.78 (td, J =
7.7, 7.2, 1.5 Hz, 1H), 7.02 (t, J = 54.3 Hz, 1H), 3.21 (s, 3H),
3.09 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 170.4, 151.2
(t, J = 26.7 Hz), 142.8, 135.3, 134.4, 130.7, 130.2, 129.7,
129.0, 125.2 (t, J = 4.4 Hz), 124.4, 123.0, 122.4, 121.6 (t, J =
1.7 Hz), 118.3 (t, J = 243.5 Hz), 39.7, 35.6. 19F NMR (471
MHz, CDCl3) δ -110.6 (d, J = 54.0 Hz).
8-chloro-6-(difluoromethyl)phenanthridine
(3ah).15
Following general procedure, 3ah was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (18.5 mg,
70%). 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J = 8.9 Hz, 1H),
8.43 (d, J = 1.8 Hz, 1H), 8.40 (dd, J = 8.2, 1.3 Hz, 1H), 8.09
(dd, J = 7.8, 1.4 Hz, 1H), 7.72 (dd, J = 8.9, 2.1 Hz, 1H), 7.69
(td, J = 7.2, 1.4 Hz, 1H), 7.66 (td, J = 7.2, 1.3 Hz, 1H), 6.90 (t,
J = 54.3 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 150.3 (t,
J = 26.9 Hz), 142.3, 133.9, 132.1, 131.8, 130.7, 129.4, 129.1,
125.7 (t, J = 4.7 Hz), 124.3, 124.0, 123.1 (t, J = 1.8 Hz), 122.0,
118.1 (t, J = 243.6 Hz). 19F NMR (471 MHz, CDCl3) δ -111.1
(d, J = 54.0 Hz).
6-(difluoromethyl)-8-(methylsulfonyl)phenanthridine
(3an).15 Following general procedure, 3an was purified by
silica gel chromatography (PE/EA = 4/1) as a white solid (21.2
mg, 69%). 1H NMR (500 MHz, CDCl3) δ 9.19 (s, 1H), 8.89 (d,
J = 8.6 Hz, 1H), 8.67 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 8.6 Hz,
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The Journal of Organic Chemistry
1H), 8.29 (d, J = 8.0 Hz, 1H), 7.93 (t, J = 7.5 Hz, 1H), 7.88 (t,
CDCl3) δ -111.3 (d, J = 54.6 Hz). HRMS (ESI) m/z [M+H]+
calculated for C15H9F2NO2 274.0674; found 274.0671.
J = 7.5 Hz, 1H), 7.06 (t, J = 54.2 Hz, 1H), 3.22 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 151.3 (t, J = 26.8 Hz), 143.3, 139.6,
137.0, 131.0, 130.9, 129.6, 128.3, 126.9 (t, J = 4.2 Hz), 124.3,
123.7, 122.8, 121.8, 117.9 (t, J = 243.8 Hz), 44.8. 19F NMR
(471 MHz, CDCl3) δ -110.3 (d, J = 54.1 Hz).
1
2
3
4
5
6
7
8
6-(difluoromethyl)-3-methylphenanthridine
(3ba).15
Following general procedure, 3ba was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (19.2 mg,
79%). 1H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 8.3 Hz, 1H),
8.47 (d, J = 8.2 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H),
7.78 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.62 (ddd, J = 8.2, 7.1, 1.0
Hz, 1H), 7.48 (dd, J = 8.3, 1.4 Hz, 1H), 6.94 (t, J = 54.4 Hz,
1H), 2.51 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 151.3 (t,
J = 26.5 Hz), 142.5, 139.4, 133.9, 131.2, 130.4, 130.0, 127.3,
126.4 (t, J = 4.1 Hz), 122.6, 122.2, 122.1 (t, J = 1.7 Hz), 121.9,
118.3 (t, J = 243.4 Hz), 21.5. 19F NMR (471 MHz, CDCl3) δ -
111.0 (d, J = 54.4 Hz).
6-(difluoromethyl)-10-methoxyphenanthridine
(3ao).15
Following general procedure, 3ao was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (9.4 mg,
36%). 1H NMR (500 MHz, CDCl3) δ 9.47 (dd, J = 8.4, 1.4 Hz,
1H), 8.19 – 8.11 (m, 2H), 7.74 – 7.65 (m, 2H), 7.64 (t, J = 8.1
Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.98 (t, J = 54.4 Hz, 1H),
4.10 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 158.3, 151.0
(t, J = 25.8 Hz), 143.0, 130.4, 128.5, 128.4, 128.0, 128.0,
124.8, 124.5, 124.3, 118.5, 118.5 (t, J = 4.7 Hz), 118.5 (t, J =
244.1 Hz), 112.1, 55.9. 19F NMR (471 MHz, CDCl3) δ -111.6
(d, J = 54.5 Hz).
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6-(difluoromethyl)-3-methoxyphenanthridine
(3bb).15
Following general procedure, 3bb was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (19.5 mg,
75%). 1H NMR (500 MHz, CDCl3) δ 8.54 (t, J = 9.8 Hz, 2H),
8.45 (d, J = 9.1 Hz, 1H), 7.84 (ddd, J = 8.3, 7.1, 1.1 Hz, 1H),
7.66 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H),
7.37 (dd, J = 9.0, 2.7 Hz, 1H), 7.01 (t, J = 54.4 Hz, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 160.3, 151.7 (t, J = 26.2
Hz), 144.1, 134.0, 131.2, 126.7, 126.3 (t, J = 4.1 Hz), 123.3,
121.9, 121.5, 119.9, 119.1, 118.2 (t, J = 243.5 Hz), 110.0, 55.7.
19F NMR (471 MHz, CDCl3) δ -111.2 (d, J = 54.2 Hz).
6-(difluoromethyl)-7-methoxyphenanthridine
(3ap).15
Following general procedure, 3ap was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (10.2 mg,
40%). 1H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 7.8 Hz, 1H),
8.30 (d, J = 8.7 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.81 – 7.75
(m, 2H), 7.74 – 7.70 (m, 1H), 7.70 (t, J = 54.8 Hz, 1H), 7.13
(d, J = 8.0 Hz, 1H), 4.08 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 157.2, 149.9 (t, J = 20.2 Hz), 142.5, 135.8, 131.7,
130.8, 129.3, 128.4, 124.2, 122.5, 115.1, 114.9, 112.1 (t, J =
240.7 Hz), 108.6, 56.1. 19F NMR (471 MHz, CDCl3) δ -118.8
(d, J = 54.8 Hz).
6-(difluoromethyl)-3-fluorophenanthridine
(3bc).15
Following general procedure, 3bc was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (18.6 mg,
(3ap').15
75%). H NMR (500 MHz, CDCl3) δ 8.60 – 8.54 (m, 2H),
1
6-(difluoromethyl)-9-methoxyphenanthridine
Following general procedure, 3ap' was purified by silica gel
8.54 – 8.48 (m, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.83 (d, J = 9.3
Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.01
(t, J = 54.4 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ
162.7 (d, J = 249.4 Hz), 152.6 (t, J = 26.6 Hz), 143.6 (d, J =
12.0 Hz), 133.6, 131.6, 127.6, 126.5 (t, J = 4.3 Hz), 124.1 (d, J
= 9.4 Hz), 122.1, 121.9 (d, J = 1.3 Hz), 121.6 (d, J = 1.8 Hz),
118.1 (t, J = 243.5 Hz), 117.8 (d, J = 23.8 Hz), 115.0 (d, J =
20.6 Hz). 19F NMR (471 MHz, CDCl3) δ -111.3 (d, J = 54.6
Hz, 2F), -111.6 (m, 1F).
chromatography (PE/EA = 30/1) as a white solid (12.0 mg,
1
47%). H NMR (500 MHz, CDCl3) δ 8.56 – 8.47 (m, 2H),
8.19 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.78 (t, J =
8.2, 1.3 Hz, 1H), 7.73 (t, J = 8.2, 1.3 Hz, 1H), 7.35 (dd, J = 9.1,
2.5 Hz, 1H), 7.01 (t, J = 54.4 Hz, 1H), 4.07 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 161.7, 150.9 (d, J = 26.4 Hz),
136.2, 130.5, 129.2, 128.4 (t, J = 4.3 Hz), 128.1, 124.7, 122.2,
118.3 (d, J = 243.1 Hz), 118.1, 117.3, 103.1, 55.6. 19F NMR
(471 MHz, CDCl3) δ -110.8 (d, J = 54.5 Hz).
3-chloro-6-(difluoromethyl)phenanthridine
(3bd).14,15
6-(difluoromethyl)-7,8,9-trimethoxyphenanthridine (3aq).
Following general procedure, 3aq was purified by silica gel
chromatography (PE/EA = 20/1) as a white solid (12.5 mg,
Following general procedure, 3bd was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (17.9 mg,
68%). 1H NMR (500 MHz, CDCl3) δ 8.55 (t, J = 7.7 Hz, 2H),
8.43 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.87 (d, J =
8.0 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.65 (dd, J = 8.8, 2.0 Hz,
1H), 6.99 (t, J = 54.3 Hz, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 152.5 (t, J = 26.6 Hz), 143.0, 134.7, 133.3, 131.6,
129.7, 129.1, 128.7, 128.0, 126.5 (t, J = 4.3 Hz), 123.4, 123.3,
122.2, 118.1 (t, J = 243.8 Hz). 19F NMR (471 MHz, CDCl3) δ
-111.3 (d, J = 54.4 Hz).
1
39%). Mp: 124.7-126.1 °C; H NMR (500 MHz, CDCl3) δ
8.41 (d, J = 7.8 Hz, 1H), 8.26 – 8.20 (dd, J = 8.1, 0.8 Hz, 1H),
7.76 (s, 1H), 7.74 – 7.69 (m, 1H), 7.68 – 7.63 (m, 1H), 7.65 (t,
J = 54.9 Hz, 1H), 4.13 (s, 3H), 4.12 (s, 3H), 3.99 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 156.8, 150.7, 149.0 (t, J =
20.6 Hz), 142.5, 142.4, 131.8, 130.9, 128.9, 128.0, 123.8,
121.8, 113.9, 112.3 (t, J = 240.5 Hz), 98.7, 61.7, 61.1, 56.2.
19F NMR (471 MHz, CDCl3) δ -118.1 (d, J = 55.0 Hz). HRMS
(ESI) m/z [M+H]+ calculated for C17H16 F2NO3 320.1093;
found 320.1092.
6-(difluoromethyl)-3-(trifluoromethyl)phenanthridine
(3be).14,15 Following general procedure, 3be was purified by
silica gel chromatography (PE/EA = 30/1) as a white solid
1
6-(difluoromethyl)-[1,3]dioxolo[4,5-j]phenanthridine
(3ar).12a Following general procedure, 3ar was purified by
silica gel chromatography (PE/EA = 30/1) as a white solid
(16.4mg, 55%). H NMR (500 MHz, CDCl3) δ 8.86 (s, 1H),
8.79 (d, J = 8.7 Hz, 1H), 8.62 (d, J = 8.1 Hz, 1H), 8.25 (d, J =
8.0 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.87 (t, J = 7.5 Hz, 1H),
7.83 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 54.2 Hz, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ 151.2 (t, J = 26.8 Hz), 143.0, 135.9,
130.8, 130.3, 129.7 (d, J = 32.9 Hz), 129.3, 127.1 (q, J = 3.2
Hz), 124.0 (q, J = 4.0 Hz), 124.0, 123.5, 123.8 (q, J = 272.4
Hz), 122.5, 121.7 (t, J = 1.8 Hz), 118.1 (t, J = 243.6 Hz). 19F
NMR (471 MHz, CDCl3) δ -63.0 (s, 3F), -110.4 (d, J = 54.2
Hz, 2F).
1
(19.4 mg, 71%). Mp: 179.8-181.6 °C; H NMR (500 MHz,
CDCl3) δ 8.37 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H),
7.94 (s, 1H), 7.88 (s, 1H), 7.76 – 7.66 (m, 2H), 6.98 (t, J =
54.4 Hz, 1H), 6.19 (s, 2H). 13C{1H} NMR (126 MHz, CDCl3)
δ 151.5, 149.9 (t, J = 26.3 Hz), 148.5, 142.2, 132.0, 130.4,
128.4, 128.2, 125.1, 122.0, 118.9, 118.6 (t, J = 243.5 Hz),
103.6 (t, J = 4.9 Hz), 102.2, 100.2. 19F NMR (471 MHz,
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6-(difluoromethyl)-3-nitrophenanthridine (3bf).15 Following 124.6, 123.7, 122.9, 121.7, 117.1 (t, J = 243.0 Hz). 19F NMR
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2
3
4
5
6
7
8
general procedure, 3bf was purified by silica gel
chromatography (PE/EA = 10/1) as a white solid (8.8 mg,
32%). 1H NMR (500 MHz, CDCl3) δ 8.96 (d, J = 2.3 Hz, 1H),
8.63 (d, J = 8.9 Hz, 2H), 8.57 (d, J = 8.3 Hz, 1H), 8.44 (dd, J =
9.0, 2.4 Hz, 1H), 7.96 – 7.92 (m, 1H), 7.84 – 7.80 (m, 1H),
6.94 (t, J = 54.2 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ
153.8 (t, J = 26.9 Hz), 147.6, 141.8, 132.7, 132.2, 129.9, 129.4,
126.9 (t, J = 4.4 Hz), 126.3, 123.7, 123.3, 123.3, 122.2, 117.8
(t, J = 244.1 Hz). 19F NMR (471 MHz, CDCl3) δ -111.6 (d, J =
54.3 Hz).
(471 MHz, CDCl3) δ -114.6 (d, J = 54.9 Hz).
6-(difluoromethyl)benzo[4,5]thieno[3,2-k]phenanthridine
(3cd).15 Following general procedure, 3cd was purified by
silica gel chromatography (PE/EA = 20/1) as a white solid
1
(16.5 mg, 49%). H NMR (500 MHz, CDCl3) δ 9.14 (d, J =
8.3 Hz, 1H), 8.70 (d, J = 8.7 Hz, 1H), 8.50 (d, J = 8.7 Hz, 1H),
8.32 (t, J = 8.5 Hz, 2H), 8.02 (dd, J = 6.2, 2.2 Hz, 1H), 7.92 (t,
J = 7.6 Hz, 1H), 7.87 (t, J = 7.5 Hz, 1H), 7.62 – 7.56 (m, 2H),
7.12 (t, J = 54.4 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ
151.4 (t, J = 26.2 Hz), 143.4, 140.2, 137.9, 134.2, 134.0, 131.1,
130.4, 128.9, 128.8, 127.8, 125.5, 125.2, 124.5, 122.8 (t, J =
4.9 Hz), 122.3, 122.3, 122.2, 121.3, 118.6 (t, J = 244.2 Hz). 19F
NMR (471 MHz, CDCl3) δ -110.1 (d, J = 54.6 Hz).
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Methyl
6-(difluoromethyl)phenanthridine-3-carboxylate
(3bg). Following general procedure, 3bg was purified by silica
gel chromatography (PE/EA = 10/1) as a white solid (18.7 mg,
1
62%). Mp: 117.2-119.1 °C; H NMR (400 MHz, CDCl3) δ
Methyl
1-(difluoromethyl)-4-phenylisoquinoline-3-
8.89 (d, J = 1.7 Hz, 1H), 8.70 (d, J = 8.3 Hz, 1H), 8.62 (t, J =
7.3 Hz, 2H), 8.37 (dd, J = 8.6, 1.8 Hz, 1H), 7.96 (t, J = 7.7 Hz,
1H), 7.83 (t, J = 7.7 Hz, 1H), 7.04 (t, J = 54.3 Hz, 1H), 4.50 (q,
J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 166.0, 152.3 (t, J = 26.6 Hz), 141.9, 133.2,
132.5, 131.6, 130.9, 128.8, 128.5, 128.1, 126.6 (t, J = 4.3 Hz),
123.0, 122.4, 118.1 (t, J = 243.8 Hz), 61.5, 14.4. 19F NMR
(376 MHz, CDCl3) δ -110.8 (d, J = 54.3 Hz). HRMS (ESI)
m/z [M+H]+ calculated for C17H14F2NO2 302.0988; found
302.0980.
carboxylate (3da). Following general procedure, 3da was
purified by silica gel chromatography (PE/EA = 10/1) as a
1
white solid (19.8 mg, 63%). Mp: 119.1-120.8 °C; H NMR
(400 MHz, CDCl3) δ 8.64 (d, J = 8.3 Hz, 1H), 7.83 – 7.77 (m,
1H), 7.77 – 7.71 (m, 2H), 7.58 – 7.51 (m, 3H), 7.40 – 7.33 (m,
2H), 7.09 (t, J = 54.1 Hz, 1H), 3.73 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 166.8, 150.6 (t, J = 27.2 Hz), 140.1,
137.0, 136.9, 135.4, 131.3, 129.5, 129.5, 128.4, 128.3, 127.3,
125.5, 125.4 (t, J = 4.0 Hz), 117.8 (t, J = 242.8 Hz), 52.6. 19
F
NMR (376 MHz, CDCl3) δ -109.6 (d, J = 54.4 Hz). HRMS
(ESI) m/z [M+H]+ calculated for C18H14F2NO2 314.0988;
found 314.0986.
6-(difluoromethyl)indolo[1,2-a]quinoxaline
(3ca).
Following general procedure, 3ca was purified by silica gel
chromatography (PE/EA = 20/1) as a white solid (20.9 mg,
78%). Mp: 112.0-114.1 °C; H NMR (500 MHz, CDCl3) δ
Methyl 1-(difluoromethyl)-7-methyl-4-(p-tolyl)isoquinoline-
3-carboxylate (3db). Following general procedure, 3db was
purified by silica gel chromatography (PE/EA = 10/1) as a
1
8.47 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 8.7 Hz, 1H), 8.01 (t, J =
9.3 Hz, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H),
7.52 – 7.42 (m, 3H), 6.79 (t, J = 54.1 Hz, 1H). 13C{1H} NMR
(126 MHz, CDCl3) δ 148.8 (t, J = 27.4 Hz), 134.4, 132.6,
131.1, 131.0, 130.2, 129.2, 125.1, 124.9, 124.3, 123.2, 123.1,
1
white solid (15.0 mg, 44%). Mp: 130.5-131.7 °C; H NMR
(500 MHz, CDCl3) δ 8.38 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H),
7.56 (dd, J = 8.7, 1.5 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.25 –
7.20 (m, 2H), 7.06 (t, J = 54.2 Hz, 1H), 3.75 (s, 3H), 2.63 (s,
3H), 2.49 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 167.0,
149.5 (t, J = 27.1 Hz), 134.0, 139.3, 138.0, 137.1, 135.4, 133.5,
132.5, 129.3, 129.0, 127.1, 125.8, 124.1 (t, J = 3.8 Hz), 118.0
(t, J = 242.5 Hz), 52.6, 22.1, 21.4. 19F NMR (376 MHz, CDCl3)
δ -109.9 (d, J = 54.0 Hz). HRMS (ESI) m/z [M+H]+ calculated
for C20H18F2NO2 342.1301; found 342.1300.
115.5 (t, J = 240.5 Hz), 114.8, 114.4, 101.2 (t, J = 2.7 Hz). 19
F
NMR (376 MHz, CDCl3) δ -117.9 (d, J = 54.3 Hz). HRMS
(ESI) m/z [M+H]+ calculated for C16H11F2N2 269.0885; found
269.08790.
4-(difluoromethyl)pyrrolo[1,2-a]quinoxaline
(3cb).
Following general procedure, 3cb was purified by silica gel
chromatography (PE/EA = 30/1) as a white solid (11.6 mg,
53%). Mp: 92.8-94.5 °C; H NMR (500 MHz, CDCl3) δ 7.98
Methyl
1-(difluoromethyl)-7-fluoro-4-(4-
(3dc).Following
1
fluorophenyl)isoquinoline-3-carboxylate
(dd, J = 2.6, 1.1 Hz, 1H), 7.97 (dd, J = 8.1, 1.3 Hz, 1H), 7.85
(dd, J = 8.3, 1.0 Hz, 1H), 7.57 (td, J = 7.7, 1.3 Hz, 1H), 7.46
(td, J = 7.7, 1.3 Hz, 1H), 7.21 – 7.16 (m, 1H), 6.94 (dd, J = 4.0,
2.7 Hz, 1H), 6.71 (t, J = 54.3 Hz, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 147.3 (t, J = 27.3 Hz), 134.5, 130.6, 129.3,
128.0, 125.5, 122.0, 115.4 (t, J = 242.3 Hz), 115.0, 114.6,
113.8, 107.7 (t, J = 2.4 Hz). 19F NMR (471 MHz, CDCl3) δ -
117.7 (d, J = 54.5 Hz). HRMS (ESI) m/z [M+H]+ calculated
for C12H9F2N2 219.0729; found 219.0724.
6-(difluoromethyl)benzo[4,5]thieno[3,2-c]quinolone (3cc).15
Following general procedure, 3cc was purified by silica gel
chromatography (PE/EA = 20/1) as a white solid (14.1 mg,
49%). 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J = 8.5 Hz, 1H),
8.16 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 4.0, 0.8 Hz, 1H), 7.93 –
7.88 (m, 1H), 7.71 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.64 – 7.60
(m, 1H), 7.51 (td, J = 8.3, 7.7, 1.4 Hz, 1H), 7.47 (td, J = 7.6,
1.3 Hz, 1H), 7.08 (t, J = 54.8 Hz, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 147.9, 145.9 (t, J = 28.6 Hz), 142.0, 137.7,
132.4, 129.4, 128.9, 127.6, 126.0, 124.9 (t, J = 8.0 Hz), 124.8,
general procedure, 3dc was purified by silica gel
chromatography (PE/EA = 10/1) as a white solid (14.7 mg,
1
42%). Mp: 131.8-134.0 °C; H NMR (500 MHz, CDCl3) δ
8.26 – 8.20 (m, 1H), 7.71 (dd, J = 9.4, 5.4 Hz, 1H), 7.52 (ddd,
J = 9.5, 7.9, 2.5 Hz, 1H), 7.33 – 7.28 (m, 2H), 7.25 – 7.21 (m,
2H), 7.03 (t, J = 54.0 Hz, 1H), 3.74 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 166.4, 162.9 (d, J = 248.8 Hz), 162.1 (d,
J = 254.3 Hz), 150.2 (td, J = 27.3, 5.7 Hz), 139.8, 135.9, 134.2,
131.2 (d, J = 8.1 Hz), 130.9 (d, J = 3.5 Hz), 130.1 (d, J = 9.0
Hz), 126.6 (d, J = 9.7 Hz), 122.1 (d, J = 25.3 Hz), 118.4 (d, J
= 242.7 Hz), 115.7 (d, J = 21.7 Hz), 109.6 (dt, J = 23.1, 4.2
Hz), 52.7. 19F NMR (471 MHz, CDCl3) δ -106.6 (m, 1F), -
110.83 (d, J = 54.9 Hz, 2F), -113.1 (m, 1F). HRMS (ESI) m/z
[M+H]+ calculated for C18H12F4NO2 350.0799; found
350.0795.
Methyl
7-bromo-4-(4-bromophenyl)-1-
(difluoromethyl)isoquinoline-3-carboxylate (3dd). Following
general procedure, 3dd was purified by silica gel
chromatography (PE/EA = 10/1) as a white solid (23.9 mg,
1
51%). Mp: 188.8-189.9 °C; H NMR (500 MHz, CDCl3) δ
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The Journal of Organic Chemistry
8.79 – 8.71 (m, 1H), 7.81 (dd, J = 9.1, 1.9 Hz, 1H), 7.70 – 7.64
ACKNOWLEDGMENT
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2
3
4
5
6
7
8
(m, 2H), 7.53 (d, J = 9.1 Hz, 1H), 7.23 – 7.17 (m, 2H), 7.02 (t,
J = 53.9 Hz, 1H), 3.76 (s, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 166.2, 149.9 (t, J = 27.6 Hz), 140.1, 135.8, 135.4,
135.2, 133.7, 131.8, 131.0, 128.6, 127.8 (t, J = 4.4 Hz), 126.3,
124.7, 123.1, 117.5 (t, J = 243.0 Hz), 52.8. 19F NMR (471
MHz, CDCl3) δ -110.2 (d, J = 53.9 Hz). HRMS (ESI) m/z
[M+H]+ calculated for C18H12Br2F2NO2 469.9198, 471.9177,
473.9157; found 469.9193, 471.9176, 473.9155.
This work was financially supported by the Natural Science
Foundation of Shenzhen (No. KQJSCX20180328095508144)
and the Natural Science Foundation of Guangdong Province (No.
2020A1515010874). We thank the Instrumental Analysis Center
of Shenzhen University for analytical work.
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Biology, Blackwell, Oxford, 2009, and references therein.(b) Wang, J.;
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Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in pharmaceutical
industry: fluorine-containing drugs introduced to the market in the last
decade (2001–2011), Chem. Rev. 2014, 114, 2432-2506, and
references therein. (c) Bassetto, M.; Ferla, S.; Pertusati, F.
Polyfluorinated groups in medicinal chemistry. Future Med. Chem.
2015, 7, 527-549, and references therein.
(2) (a) Goure, W. F.; Leschinsky, K. L.; Wratten, S. J.; Chupp, J. P.
Synthesis and herbicidal activity of N-substituted 2,6-
bis(polyfluoromethyl)dihydropyridine-3,5-dicarboxylates. J. Agric.
Food Chem. 1991, 39, 981-986. (b) Pérez, R. A.; Sánchez-Brunete, C.;
Miguel, E.; Tadeo, J. L. Analytical methods for the determination in
soil of herbicides used in forestry by GC−NPD and GC/MS. J. Agric.
Food Chem. 1998, 46, 1864-1869.
Methyl 4-(difluoromethyl)furo[3,2-c]pyridine-6-carboxylate
(3de). Following general procedure, 3de was purified by silica
gel chromatography (PE/EA = 10/1) as a white solid (7.7 mg,
34%). Mp: 87.3-89.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.46 –
8.41 (m, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 2.0, 1.1
Hz, 1H), 6.95 (t, J = 54.5 Hz, 1H), 4.06 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 165.2, 160.8, 149.4, 146.7 (t, J = 29.2
Hz), 142.6, 124.7, 115.0 (t, J = 239.8 Hz), 111.2, 105.4 (t, J =
2.2 Hz), 53.2. 19F NMR (471 MHz, CDCl3) δ -114.0 (d, J =
54.5 Hz). HRMS (ESI) m/z [M+H]+ calculated for
C10H8F2NO3 228.0467; found 228.0462.
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Methyl
1-(difluoromethyl)-9-methyl-9H-pyrido[3,4-
b]indole-3-carboxylate (3df). Following general procedure,
3df was purified by silica gel chromatography (PE/EA = 10/1)
(3) (a) Kirsch, P.; Bremer, M. Nematic liquid crystals for active
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1
as a white solid (12.0 mg, 41%). Mp: 161.0-163.0 °C; H
NMR (500 MHz, CDCl3) δ 8.98 (s, 1H), 8.21 (d, J = 7.8 Hz,
1H), 7.70 (ddd, J = 8.3, 7.2, 1.1 Hz, 1H), 7.57 (d, J = 8.4 Hz,
1H), 7.41 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 54.7 Hz, 1H), 4.15 (t,
J = 2.2 Hz, 3H), 4.08 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 165.9, 143.0, 135.7, 135.6, 134.8 (t, J = 29.8 Hz),
131.9, 129.7, 121.5, 121.3, 121.1, 119.7, 118.2 (d, J = 240.4
Hz), 110.3, 52.9, 32.8 (t, J = 8.2 Hz). 19F NMR (471 MHz,
CDCl3) δ -104.5 (d, J = 54.7 Hz). HRMS (ESI) m/z [M+H]+
calculated for C15H13F2N2O2 291.0940; found 291.0937.
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Cyclic Voltammetry Studies of reagent 2
The cyclic voltammetry measurements were performed on a
CHI660E electrochemical workstation, using a standard three-
electrode setup with a platinum wire counter electrode, and a
glassy carbon electrode as the working electrode) and a SCE
(the saturated calomel electrode) as the reference electrode.
The solution were prepared with reagent 2 (0.05 mmol) in the
supporting electrolyte n-Bu4NPF6 in dry acetonitrile (50 mL,
0.1 M). Solutions thoroughly bubbled with dry nitrogen for 15
min to remove oxygen before any experiment and kept under
positive pressure of nitrogen. Cyclic voltammetry (CV) with
the following settings: Scan Rates= 0.1 V/s, Sweep Segments
= 4, Sample Interval = 0.001 V, Quiet Time = 2 sec.
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)
AUTHOR INFORMATION
Corresponding Author
* E-mail: gkliu@szu.edu.cn.
ORCID
Guo-Kai Liu: 0000-0001-7617-4267
Notes
The authors declare no competing financial interest.
(7) For the progress in photochemical radical difluoromethylation,
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