Visible Light-Induced Radical Cyclization of Tertiary Bromides with Isonitriles to Construct Trifluoromethylated Quaternary Carbon Center

Article abstract of DOI:10.1021/acs.joc.8b02405

The reaction of trifluoromethylated tertiary bromides with isonitriles induced by visible light is reported. Defluorination was avoided in a radical process. This method provides an efficient approach to compounds containing a trifluoromethylated quaternary carbon center, most of which show excellent potential to be agrochemicals. In addition, the bromides were prepared from perfluoroisobutylene, which is a waste from industry, after several steps. This reaction shows a feasible transfer of harmful waste into useful compounds.

Full text of DOI:10.1021/acs.joc.8b02405

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Article
Visible Light-induced Radical Cyclization of Tertiary Bromides with
Isonitriles to Construct Trifluoromethylated Quaternary Carbon Center
Wengui Wang, Yong Guo, Ke Sun, Shoufeng Wang, Shuxiang Zhang, Chao Liu, and Qing-Yun Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02405 • Publication Date (Web): 07 Nov 2018
Downloaded from http://pubs.acs.org on November 8, 2018
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The Journal of Organic Chemistry
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Visible Light-induced Radical Cyclization of Tertiary Bromides with
Isonitriles to Construct Trifluoromethylated Quaternary Carbon Center
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*,†,‡
*,§
II
†,‡
†,‡
§
Wengui Wang,
Yun Chen
Yong Guo, Ke Sun, Shoufeng Wang, Shuxiang Zhang, Chao Liu and Qing-
*
,§
†School of Chemistry and Chemical Engineering, University of Jinan, 336 West Road of Nan Xinzhuang, Jinan, 250022,
China
‡Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical materials, 336 West Road of Nan Xinzhuang,
Jinan, 250022, China
§Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China
IIState Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Ltd,
Shenyang 110021, China
Supporting Information Placeholder
Ar2
Ar2
Ar1
O
N
O
N
visible light
NC
Ar1
COOMe
CF3
N
MeOOC
Br
MeOOC
CF3
CF3
O
N
excellently potent agrochemicals
CF3
F
F
mild conditions
CF3
moderate to excellent yields
good functional group tolerance
good bioacativities
waste from industry
ABSTRACT: The reaction of trifluoromethylated tertiary bromides with isonitriles induced by visible light is reported.
Defluorination could be avoided in a radical process. This method provides an efficient approach to compounds containing a
trifluoromethylated quaternary carbon center, most of which show excellent potential to be agrochemicals. In addition, the
bromides were prepared from perfluoroisobutylene after several steps, which is a waste from industry. This reaction shows a
feasible transfer of harmful waste into useful compounds.
with TFQC by using electrophilic reagents such as
trifluoromethylated olefins. We have showed great interest in
INTRODUCTION
Recent protocols in designing new bioactive molecules
involve the construction of trifluoromethylated quaternary
carbon center (TFQC) which combine structure feature of
taking use of α-trifluoromethylated carbanions which is a
challenging starting material with a facile defluorination
1
1
before further functionalization. Iridium catalyst, palladium
1
-3
12
13
trifluoromethyl group and quaternary carbon center.
catalyst and organocatalyst have been proved to be
successful approach to TFQC. However, normally highly
electrophilic substrates, such as electron deficient olefins are
needed, which limited the application.
Trifluoromethyl groups are widely found in pharmaceuticals
and agrochemicals because of the enhanced physicochemical
properties, including lipophilicity, metabolic stability, and
4
especially the bioavailability. Quaternary carbon centers are
To expand the chemistry to a wide scope, we design radical
reactions by using α-trifluoromethylated tertiary bromides
key structure features in many natural products and
5
biologically significant molecules. The construction of TFQC
which are derived from α-trifluoromethylated carbanions
has become an interesting topic; however, the construction of
1
(
Figure 1). The radical reactions are widely applied to alkenes
6
all-carbon quaternary center is still a field full of challenges.
and alkynes and some of the products have a moderated
antifungal activity, showing the novel strategy for
agrochemical discovery. Meanwhile, phenanthridines are an
7
8
9
Michael addition reaction, S
N
2’ reaction, cycloaddition and
1
0
transition-metal catalysis are used to synthesize compounds
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important core of many natural compounds and the
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6
construction of phenanthridines has attracted much attention.
2-Isocyano-1,1'-biphenyl and its derivatives are found to be an
useful synthon, which react with radical efficiently, resulting
catalyst
base
COOMe
CF3
O
N
N
+
solvent, rt
visible light, 12 h
Br
NC
1
4
MeOOC
N
O
in 6-substituted phenanthridines through cyclization.
Reactions of fluoalkyl radicals with 2-isocyano-1,1'-biphenyl
CF3
1a
2a
3aa
1
5
have also been reported. Herein, we report visible light-
induced cyclization of α-trifluoromethylated tertiary bromides
with isonitriles, resulting in compounds containing TFQC,
which exhibited much better bioactivity than our previously
reported substrates. This process leads to molecules diversified
bioactivities, satisfying the need for discovery agrochemical
Yield(%)b
entry catalyst
solvent base
1
2
3
4
5
6
7
8
9c
Ir(ppy)
Ir(ppy)
Ir(ppy)
3
3
3
DMF
DMF
DMF
MeCN
DCM
DCM
DCM
DCM
DCM
DCM
K
3
2
PO
4
Trace
33
36
82
92
9
K
CO
3
Na
2
CO
3
3
3
3
3
3
3
3
0
1
2
3
4
5
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8
9
0
1
2
3
4
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0
1
2
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0
1
2
3
4
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9
0
1
2
3
4
5
6
7
8
9
0
Ir(ppy)3
Ir(ppy)
Ir(dF(CF
Ir(ppy)
Ru(bpy)
2
Na CO
1
6
for a sustainable world.
3
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
Br
R
N
O
N
3
)ppy
2
6
(dtbppy)(PF )
O
R
R
N
R
O
2
(dtbppy)(PF
6
)
82
25
MeOOC
Br Previous
work
MeOOC
Br
Previous
work
F3C
CF3
CF3
3
2
Cl .6H
2
O
COOMe
Ir(ppy)
3
3
96
moderately
potent
0d
NRe
1
Ir(ppy)
Ar2
NC
agrochemicals
This work
aReaction conditions: 1a (0.24 mmol, 1.2 eq), 2a (0.2 mmol,
.0 eq), catalyst (0.004 mmol, 2 mol%), base (0.4 mmol, 2 eq),
Ar1
1
solvent (2 mL). The mixture was irradiated by a 24 W
b
Ar2
fluorescent lamp for 12 h under room temperature. Yields
19
COOMe
CF3
were determined by F NMR using 4-
Ar1
N
c
(
trifluoromethoxy)anisole as internal standard. 3 eq base was
d
e
added. 3 eq base in darkness. No reaction.
O
N
enhanced
potent agrochemicals
With the optimal conditions in hands, substrates scope was
explored. Isonitriles with different substituents could react
smoothly with trifluoromethylated tertiary bromide 1a to yield
TFQC-containing compounds 3 (Table 2). When the hydrogen
at 4’-position was substituted by other groups, the reaction
furnished the desiring products in good to excellent yields
Figure 1. Visible light –induced construction of TFQC.
RESULT AND DISCUSSION
To begin our study, we chose trifluoromethylated tertiary
bromide 1a and 2-isocyano-1,1'-biphenyl 2a as model
substrates. Systematic condition screening was carried out
(Table 1). The reaction was initially carried out in anhydrous
t
(3ab-3ai). Both alkyl and aryl could be tolerated, such as Bu,
Ph and 1-naphthyl (3ab, 3ae, 3af). Electron-donating groups,
such as MeO (3ac) and MeS (3ad) are compatible under this
condition. If electron-withdrawing groups were introduced
into isonitriles, the reaction could also go smoothly with high
DMF using Ir(ppy)
However, only trace of the product was detected by F NMR
Table1, entry 1). We thought that maybe a stronger base was
needed. To our delight, when the base changed to K CO , the
desired product was obtained in 33% yield (Table 1, entry 2).
Utilization of Na CO as base showed minor improvement of
3 3 4
as catalyst and K PO as the base.
1
9
(
yields. The substitutents could be SO Me (3ag), COOMe (3ah)
2
2
3
and CF (3ai). However, when the hydrogen at 2’-positon was
3
replaced by other groups, such as methyl and fluorine,
2
3
decrease of the yield was observed (3aj, 3ak). The lowered
yields maybe caused by the occupation of 2’-position. Only
one ortho position was available on the aryl ring, which led to
a less chance for the approximation of the generated radical
and the reactive site. This was also the outcome of isonitriles
containing benzohetercyclic ring part (3al, 3am, 3an).
Substituents in the 3’-position could also be tolerated, such as
the yield (Table 1, entry 3). Then, different solvents were
examined. Changing of solvent resulted in high yield.
Reaction in MeCN afforded 82% yield (Table 1, entry 4).
Yield was further improved to 92% when the reaction was
carried out in DCM (Table 1, entry 5). After establishing
DCM as the proper solvent, the photoredox catalysts were
studied. Both Ir and Ru complexes were employed (Table 1,
Me (3ao), and CF (3ap). 3ao was the main product showed
3
entry 5-8). However, both Ir(dF(CF
3
)ppy)
2
(dtbppy)(PF
6
) and
was
by the 19F NMR of the reaction system. Different atom or
Ru(bpy) Cl .5H gave low yield. And Ir(ppy)
3
2
2
O
3
groups on the aryl ring substituted by the isocyano group
could also subject to the reaction condition (3aq-3au). Both
electron-donating groups and electron-withdrawing groups or
atom could be introduced into substrates, such as Me, F, Cl
and NO2.
confirmed as the most efficient catalyst. We wondered if
increasing the use of base could give higher yields. Results
showed that increasing of the base loading led to slightly
higher yield (Table 1, entry 9). If 3 eq base was used, only a
small increase of yield was observed. Control experiment was
carried out under the optimal conditions without visible light
and no product was obtained (Table 1, entry 10), indicating
that visible light was necessary for this process.
To further explore the scope of the substrates, reactions were
performed using different trifluoromethylated tertiary
bromides with different substitutents on the oxazolyl ring
(
Table 3). Both alkyl (3ba-3fa) and aryl (3ga) could be
Table 1. Optimization of reaction conditions.a
tolerated under the optimal conditions. Reactions of the
substrates containing stereocenters gave products 3ca-3ga in
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The Journal of Organic Chemistry
using as fungicide. The research of the insecticidal activity and
high isolated yields, although poor diastereoselectivities were
1
2
3
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8
9
1
1
1
1
1
1
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1
2
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2
3
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5
6
o
b
s
e
r
v
e
d
b
y
herbicidal activity showed that a few of the ob
Table 2. Visible light induced cyclization with various
isonitriles.
Table 3. Visible light induced cyclization with various
a,b
a,b
bromides.
3
aa, R = H, 96% (81%)
3ab, R = tBu, 85% (79%)
ac, R = OMe, 88% (79%)
ad, R = SMe, 97% (89%)
R
R1
3
R2
3
COOMe
Ir(ppy)3 (2 mol%)
CF3
COOMe
CF3
3ae
,
R - Ph, 97% (84%)
O
N
N
N
Na2CO3 (3 eq)
3af
,
R = 1-naphthyl, 91% (67%)
3ag, R = SO2Me, 99% (71%)
3ah, R = COOMe, 87% (83%)
+
DCM, rt
visible light, 12 h
N
O
N
O
MeOOC
Br
CF3
NC
2a
3
ai, R = CF3, 96% (90%)
R1
R2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
Me
F
F
O
S
COOMe
CF3
COOMe
CF3
COOMe
CF3
COOMe
CF3
N
N
N
N
COOMe
CF3
COOMe
CF3
COOMe
N
N
O
N
O
N
O
N
O
N
N
N
CF3
N
O
3aj
3ak
3al
3am
O
N
O
3
9% (31%)
75% (47%)
Me
59% (51%)
CF3
79% (54%)
Ph
3ba
3ca
3da
S
94% (75%)
87% (81%)
88% (73%)
S
CF3
Me
COOMe
CF3
COOMe
CF3
COOMe
CF3
COOMe
CF3
N
N
N
N
N
COOMe
CF3
COOMe
CF3
N
COOMe
CF3
N
N
O
N
O
N
O
O
N
N
O
N
O
3an
3ao
3ap
3aq
N
O
7
0% (69%)
71% (53%)
97% (91%)
86% (72%)
Ph
3fa
97% (72%)
3
ea
3ga
Cl
F
F
O2N
91% (71%)
92% (73%)
COOMe
CF3
COOMe
CF3
COOMe
COOMe
CF3
N
N
N
N
Cl
N
N
F
N
N
CF3
F
aStandard conditions: 1 (0.24 mmol, 1.2 eq), 2a (0.2 mmol, 1.0
eq), Ir(ppy) (0.004 mmol, 2 mol%), Na CO (0.6 mmol, 3 eq),
3 2 3
O
O
O
O
3ar
3as
3at
3au
9
8% (90%)
95% (63%)
96% (91%)
84% (72%)
DCM (2 mL). The mixture was irradiated by a 24 W fluorescent
lamp for 12 h under room temperature. bYields were determined
aStandard conditions: 1a (0.24 mmol, 1.2 eq), 2 (0.2 mmol, 1.0
eq), Ir(ppy) (0.004 mmol, 2 mol%), Na CO (0.6 mmol, 3 eq),
DCM (2 mL). The mixture was irradiated by a 24 W fluorescent
lamp for 12 h under room temperature. Yields were determined
by F NMR using 4-(trifluoromethoxy)anisole as internal
standard and the isolated yields were given in the parentheses.
19
by F NMR using 4-(trifluoromethoxy)anisole as internal
3
2
3
standard and the isolated yields were given in the parentheses.
b
tained compounds exhibited moderate activity. Especially, 3ah
showed high antifungal activity, moderate insecticidal activity
and herbicidal activity. It was supposed to be a potential
candidate of effective agrochemicals with comprehensive
functions. This is an encouraging result, because the active
1
9
19F NMR analyses. The two diastereomers were difficult to
separate because their Rf values were almost the same except
for 3ca. The two isomers of product 3ca could be obtained
respectively after silica chromatography. However, the
absolute configuration was not determined.
18
molecules were synthesized from perfluoroisobutylene,
which is a harmful waste from industry. Moreover, the visible
lightinduced synthesis process was very mild and many atom
or groups were tolerated.
According to previously reports,1,17 a plausible mechanism
was proposed (Scheme 1). The photocatalyst was excited to
Scheme 1. Proposed mechanism.
[fac-Ir(ppy)
3
*] and an oxidative quenching occurred. The
red
tertiary bromide 1a (E1/2 = −0.63 V vs SCE) reacted with
III
3
[fac-Ir(ppy) *], generating a radical Int I. Simultaneously, Ir
IV
was oxidized to Ir . Int I reacted with isonitriles 2a, giving an
imidoyl radical Int II. After cyclization, the radical Int III
was oxidized by Ir to form a cationic intermediate Int V, and
regenerate the photocatalyst. Deprotonation of the cation led
to the ultimate product.
IV
Creating useful and functional substance is one of the most
important objectives of synthesis. To examine the utilization
of our products, further study of the bioactivity of the products
was carried out (Table 4). To our delight, several products
exhibited good activity. Cucumber downy mildew is a serious
plant disease damage. Our 11 compounds could effectively
control pseudoperonospora cubenis with dosage of 400 mg/L.
This result showed excellent potential of these compounds
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The Journal of Organic Chemistry
Page 4 of 14
1
8
3ca-1
3ca-2
3da
95
85
100
80
50
80
0
0
5
0
N
O
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
19
20
21
22
0
50
0
15
5
0
Br
COOMe
28.6
10
0
CF3
1a
3ea
0
0
0
0
0
N
O
IrIII*
Br-
+
3fa
37.1
0
0
0
visible light
F3C
COOMe
Int I
2
3
3ga
20
0
a
b
The concentration was 400 mg/L. The concentration was 600
c
2
CF3
mg/L. The results were given under 1000 g a.i./hm .
COOMe
IrIII
IrIV
N
2a
EXPERIMENTAL SECTION
General Procedure for the Preparation of Amines (GP1).
A 24 W CFL was used as light source. All reactions were
2
carried out with a standard Schlenk tube under N . The
O
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Int IV
base
distance from the light source to the irradiation vessel was 3
CF3
COOMe
CF3
COOMe
CF3
COOMe
cm. Compound 1 was prepared according to reported methods
N
N
N
1
developed by our group. DCM was purified by distillation
2
over CaH . THF was distilled under argon from sodium
O
N
O
N
O
N
benzophenone ketyl just prior to use. Column chromatography
was performed using silica gel (mesh 300− 400). Melting
points were determined by an SGW X-4 microscopic melting
3aa
Int III
Int II
CONCLUSION
1
13
point meter. H NMR spectra were recorded at 400 MHz.
C
1
9
In summary, we have developed an efficient route to construct
TFQC-containing compounds from 2-isocyano-1,1’-biaryl and
trifluoromethylated tertiary bromides through cyclization
induced by visible light. This process went smoothly with
good to excellent yield under mild conditions. A wide range of
atom and groups are tolerated during this mild process.
Tertiary bromides with a chiral center could also react with
isocyanides without diastereoselectivity. Bioactivity was
tested, including antifungal activity, insecticidal activity and
herbicidal activity. Inspiringly, some of the products
demonstrated good bioactiveties and indicate potential
application in agrochemicals. Escapically, pseudoperonospora
cubenis could be controlled by several of our products. In
addition, this recycling use of perfluoroisobutylene was an
encouraging result, changing the industrial waste into valuable
compounds.
NMR spectra were recorded at 100 MHz. F NMR spectra
were recorded at 376 MHz. Chemical shifts for H NMR
1
spectra are reported in ppm downfield from TMS. Chemical
1
3
shifts for C NMR spectra are recorded in ppm relative to
1
3
13
residual chloroform (δ 77.0 ppm for C). C NMR was
broad-band decoupled from hydrogen nuclei. Chemical shifts
1
9
for
F
NMR are reported in ppm downfield from
). Coupling constants (J) are
fluorotrichloromethane (CFCl
3
reported in hertz. Standard abbreviations are used to denote
the signal multiplicities. Infrared spectra (IR) were recorded
with an infrared spectrometer; absorbance frequencies are
given at maximum intensity in cm . Mass spectra were
obtained on a mass spectrometer. High-resolution mass data
were recorded on a high-resolution mass spectrometer in the
EI or ESI mode.
−
1
General Procedure for the Preparation of Amines (GP1).
2-Bromoaniline (10 mmol), aryl boronic acid (12 mmol) were
added to a Schlenk flask under nitrogen atmosphere. DME (10
Table 4. Bioactivity of the TFQC-containing compounds.
entr
y
compoun
d
antifungal activity
(%)
insecticidal
herbicidal
a
b
c
activity(%)
activity(%)
mL) and aqueous solution of K
with syringe and the mixture was stirred for 30 min at room
temperature. Then PdCl (PPh (0.2 mmol, 140 mg, 0.02
equiv) was added and the mixture was stirred at 80 C for 12 h
under N atmosphere. After the reaction was complete, the
2 3
CO (2 M, 20 mL) were added
(pseudoperonospo
ra cubenis)
plutella
xylostell
a
myzus
persica
e
Zinnia
elegan
s
abutilon
theophras
ti
2
3 2
)
o
1
2
3
4
5
6
7
8
9
3aa
3ab
3ac
3ae
3af
0
0
33.3
0
0
0
0
0
10
5
0
0
0
0
0
0
0
0
0
0
0
0
2
100
100
100
0
0
0
mixture was cooled to room temperature and diluted with
EtOAc (20 mL). The aqueous layer was extracted with EtOAc
for 3 times (20 mL × 3). Then the organic phase was
0
54.5
0
0
0
20
10
10
50
0
0
0
4
combined and dried over anhydrous NaSO . The solvent was
3ag
3ah
3ai
100
100
100
100
100
50
0
0
removed under reduced pressure and the residue was purified
by column chromatography on silica gel by using petroleum
ether/EtOAc as an eluent.
42.9
0
31.3
0
3ak
3al
0
0
0
General Procedure for the Preparation of Isocyanides
(GP2). A dry flask was evacuated and backfilled with pure N
for 3 times. Amine (6 mmol, 1.0 equiv) in THF (10 mL) was
added with syringe. Then the mixture was cooled to 0 C.
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
0
0
10
0
2
3am
3ao
3aq
3as
3at
0
0
100
80
0
0
0
o
0
0
0
Acetic formic anhydride (1.5 mL), which was prepared from
the reaction of acetic anhydride (18.9 mL) with formic acid
60
0
0
0
o
50
0
0
0
(8.3 mL at 55 C for 2 h under Ar atmosphere, was added
o
3au
3ba
100
98
0
0
0
dropwise with syringe to the stirring solution at 0 C. The
mixture was allowed to warm to room temperature and stirred
for 2 h (monitored by TLC). After the reaction was complete,
0
60
0
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
the mixture was quenched and neutralized by saturated
aqueous solution of NaHCO . The aqueous layer was extracted
with EtOAc for 3 times (20 mL × 3). Then the organic phase
was combinated and dried over anhydrous MgSO . The
solvent was removed under reduced pressure and the residue
formamide was used for the subsequent dehydration without
further purification. The residue obtained (2 mmol, 1.0 eq)
2H), 7.40-7.35 (m, 1H), 7.20-7.15 (m, 2H), 6.87 (td, J = 7.4,
1.2 Hz, 1H), 6.81 (dd, J = 7.9, 1.1 Hz, 1H), 3.99 (brs, 2H).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
4'-(naphthalen-1-yl)-[1,1'-biphenyl]-2-amine. According to
GP1, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 30:1) to give target
compound as a white solid (2.361 g, yield = 80%). Mp: 141-
4
o
1
was added into a dry flask under N
Et N (10 mmol, 1.4 mL, 5.0 eq) were added. The mixture was
cooled to 0 C. POCl
2
. Then THF (5 mL) and
3
143 C. H NMR (400 MHz, CDCl ): δ 7.80 (d, J = 8.1 Hz,
1H), 7.69 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.38-
7.21 (m, 8H), 7.03-6.95 (m, 2H), 6.65 (td, J = 7.4, 1.2 Hz,
3
o
3
(4 mmol, 0.4 mL, 2.0 eq) was added
o
13
1
dropwise. The mixture was stirred at 0 C for 2 h and then
stirred under ambient temperature overnight. Once the reaction
was complete, the mixture was quenched and neutralized by
1H), 6.56 (d, J = 8.0 Hz, 1H), 3.59 (brs, 2H). C{ H} NMR
(100 MHz, CDCl ): δ 143.5, 139.8, 139.5, 138.4, 133.8, 131.5,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
130.5, 130.4, 128.9, 128.5, 128.3, 127.7, 127.2, 126.9, 126.0,
125.9, 125.8, 125.4, 118.7, 115.7. IR (KBr): 3480, 3389, 3022,
saturated aqueous solution of NaHCO
extracted with CH Cl (20 mL × 3). Then the organic phase
was combined and dried over anhydrous Na SO . The solvent
3
. The aqueous layer was
-
1613, 1591, 1575, 1487, 1449, 1394, 1003, 805, 782, 759 cm
2
2
1
+
. MS (EI, m/z, %): 295 (M , 100), 294 (35.42), 296 (28.52).
2
4
was removed and the residue was purified by column
chromatography.
HRMS (EI): calcd. for C22
295.1356.
H17N: 295.1361 (M); Found:
4'-(methylsulfonyl)-[1,1'-biphenyl]-2-amine.15a According to
GP1, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 3:1) to give target compound
General Procedure for the Construction of TFQC Induced
by Visible Light (GP3). A dry flask was evacuated and
backfilled with pure N
tertiary bromides (0.24 mmol, 1.2 eq), isocyanides (0.2 mmol,
1 eq), Ir(ppy) (0.004 mol, 2.62 mg, 2 mol%), Na CO (0.6
2
for 3 times. Trifluoromethylated
1
as a white solid (1.952 g, yield = 79%). H NMR (400 MHz,
3
CDCl ): δ 8.03-8.00 (m, 2H), 7.71-7.68 (m, 2H), 7.22 (td, J =
3
2
3
mmol, 63.6 mg, 3 eq) and DCM (2 ml) were added. The
mixture was stirred at room temperature under irradiation of a
8.0, 1.6 Hz, 1H), 7.12 (dd, J = 7.6, 1.6 Hz, 1H), 6.87 (td, J =
7.5, 1.1 Hz, 1H), 6.80(dd, J = 8.0, 1.2 Hz, 1H), 3.83 (brs, 2H),
3.11 (s, 3H).
2
2
4 W fluorescent lamp for 12 h. 5 mL H O and 5 mL EtOAc
was added to the reaction mixture. After separation of the
organic phase, the aqueous phase was the extracted with
EtOAc three times. The organic phase was combined and
washed with brine, dried over Na SO . The product was
2 4
obtained by column chromatography on silica gel using a
hexane/ethyl acetate mixture (hexane: EtOAc = 3:1) as eluent.
methyl 2'-amino-[1,1'-biphenyl]-4-carboxylate.19 According to
GP1, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 3:1) to give target compound
1
as a pale yellow solid (1.621 g, yield = 71%). H NMR (400
MHz, CDCl ): δ 8.13-8.10 (m, 2H), 7.57-7.54 (m, 2H), 7.19
3
(td, J = 7.8, 1.6 Hz, 1H), 7.13 (dd, J = 7.6, 1.5 Hz, 1H), 6.85
(td, J = 7.5, 1.1 Hz, 1H), 6.78 (dd, J = 8.0, 0.9 Hz, 1H), 3.94 (s,
3H), 3.77 (brs, 2H).
Experiment Data. 4'-(tert-butyl)-[1,1'-biphenyl]-2-amine.15a
According to GP1, the residue was purified by flash
chromatography (eluent: ether/EtOAc = 30:1) on silica gel to
give target compound as a white solid (1.868 g, yield = 83%).
4
'-(trifluoromethyl)-[1,1'-biphenyl]-2-amine.15a According to
1
GP1, the residue was purified by flash chromatography on
H NMR (400 MHz, CDCl
3
): δ 7.48 (dd, J = 8.1, 1.5 Hz, 2H),
silica gel (eluent: ether/EtOAc = 30:1) to give target
7
7
9
.41 (dd, J = 8.2, 1.5 Hz, 2H), 7.18-7.10 (m, 2H), 6.84 (t, J =
.4 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 3.79 (brs, 2H), 1.38 (s,
H).
1
compound as a yellow solid (1.921 g, yield = 81%). H NMR
3
(400 MHz, CDCl ): δ 7.71 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.0
Hz, 2H), 7.25–7.16 (m, 1H), 7.12 (dd, J = 7.6, 1.6 Hz, 1H),
4
'-methoxy-[1,1'-biphenyl]-2-amine.15a According to GP1, the
6.86 (td, J = 7.5, 1.2 Hz, 1H), 6.79 (dd, J = 8.1, 1.2 Hz, 1H),
residue was purified by flash chromatography on silica gel
eluent: ether/EtOAc = 30:1) to give target compound as a
19
3.77 (brs, 2H). F NMR (376 MHz, CDCl
3
): δ -58.56 (s, 3F).
(
1
yellow liquid (1.931 g, yield = 97%). H NMR (400 MHz,
CDCl ): δ 7.41-7.37 (m, 2H), 7.17-7.11 (m, 2H), 7.01-6.97 (m,
H), 6.83 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 3.86 (s,
H), 3.73 (brs, 2H).
'-methyl-[1,1'-biphenyl]-2-amine.20 According to GP1, the
residue was purified by flash chromatography on silica gel
eluent: ether/EtOAc = 30:1) to give target compound as a
2
3
2
3
(
1
yellow liquid (1.702 g, yield = 93%). H NMR (400 MHz,
CDCl ): δ 7.31-7.15 (m, 5H), 7.02 (d, J = 7.5 Hz, 1H), 6.81 (t,
J = 7.4 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 3.49 (brs, 2H), 2.18
s, 3H).
3
4'-(methylthio)-[1,1'-biphenyl]-2-amine.15a According to GP1,
the residue was purified by flash chromatography on silica gel
(
(
eluent: ether/EtOAc = 30:1) to give target compound as a
1
white solid (1.382 g, yield = 64%). H NMR (400 MHz,
CDCl ): δ 7.39 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H),
.17-7.10 (m, 2H), 6.82 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 8.0
Hz, 1H), 3.73(brs, 2H), 2.53 (s, 3H).
',4'-difluoro-[1,1'-biphenyl]-2-amine.21 According to GP1,
the residue was purified by flash chromatography on silica gel
eluent: ether/EtOAc = 30:1) to give target compound as a
2
3
7
(
1
brown solid (1.723 g, yield = 84%). H NMR (400 MHz,
CDCl ): δ 7.35 (td, J = 8.5, 6.5 Hz, 1H), 7.24–7.17 (m, 1H),
.09 (dd, J = 7.6, 1.5 Hz, 1H), 7.01–6.89 (m, 2H), 6.84 (td, J =
.5, 1.2 Hz, 1H), 6.80 (dd, J = 8.0, 1.1 Hz, 1H), 3.63 (brs, 2H).
3
[
1,1':4',1''-terphenyl]-2-amine.15a According to GP1, the
7
7
residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
19
F NMR (376 MHz, CDCl
10.82 (p, J = 7.6 Hz, 1F).
3
): δ -109.87 (q, J = 8.5 Hz, 1F), -
1
white solid (1.569 g, yield = 64%). H NMR (400 MHz,
1
3
CDCl ): δ 7.70-7.63 (m, 4H), 7.57-7.53 (m, 2H), 7.50-7.45 (m,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
2
-(dibenzo[b,d]furan-4-yl)aniline.15a According to GP1, the
(eluent: ether/EtOAc = 30:1) to give target compound as a
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
white solid (2.548 g, yield = 98%). H NMR (400 MHz,
brown solid (1.786 g, yield = 88%). H NMR (400 MHz,
CDCl ): δ 7.48-7.40 (m, 4H), 7.39-7.34 (m, 1H), 7.12-7.09 (m,
3
1
2H), 6.70-6.68 (m, 1H), 3.75 (brs, 2H).
CDCl
J = 7.4 Hz, 1H), 7.49-7.43 (m, 2H), 7.40-7.35 (m, 2H), 7.29
td, J = 7.7, 1.6 Hz, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.90 (d, J =
3
): δ 8.02-7.97 (m, 2H), 7.58 (d, J = 8.2 Hz, 1H), 7.52 (d,
3,5-difluoro-[1,1'-biphenyl]-2-amine.15a According to GP1,
the residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
(
8
.0 Hz, 1H), 3.80 (brs, 2H).
1
yellow liquid (1.968 g, yield = 96%). H NMR (400 MHz,
2
-(dibenzo[b,d]thiophen-4-yl)aniline.15a According to GP1, the
CDCl
3
): δ 7.49-7.42 (m, 4H), 7.41-7.37 (m, 1H), 6.80 (ddd, J
residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
yellow solid (2.503 g, yield = 91%). H NMR (400 MHz,
= 11.0, 8.4, 2.8 Hz, 1H), 6.72 (ddd, J = 9.1, 2.9, 1.7 Hz, 1H),
1
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3.65 (brs, 2H). F NMR (376 MHz, CDCl
): δ -125.0 (t, J =
3
1
8.8 Hz, 1F), -130.2 (d, J = 10.9 Hz, 1F).
CDCl
3
): δ 8.23-8.17 (m, 2H), 7.84-7.79 (m, 1H), 7.57 (t, J =
7
7
.6 Hz, 1H), 7.51-7.44 (m, 3H), 7.32-7.27 (m, 2H), 6.91 (t, J =
.4 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 3.68 (brs, 2H).
4-chloro-5-fluoro-[1,1'-biphenyl]-2-amine. According to GP1,
the residue was purified by flash chromatography on silica gel
(
eluent: ether/EtOAc = 30:1) to give target compound as a
1
2
-(thianthren-1-yl)aniline. According to GP1, the residue was
brown oil (1.870 g, yield = 81%). H NMR (400 MHz, CDCl
3
):
purified by flash chromatography on silica gel (eluent:
ether/EtOAc = 30:1) to give target compound as a yellow solid
δ 7.49-7.45 (m, 2H), 7.43-7.36 (m, 3H), 6.94 (d, J = 9.5 Hz,
13
1
1H), 6.77 (d, J =6.4 Hz, 1H), 3.68 (brs, 2H). C{ H} NMR
(100 MHz, CDCl ): δ 151.4 (d, J = 239.1 Hz), 140.3 (d, J =
2.3 Hz), 137.6, 129.0, 128.8, 127.8, 127.1 (d, J = 6.0 Hz),
o
1
(2.364 g, yield = 77%). Mp: 49-52 C. H NMR (400 MHz,
3
CDCl ): δ 7.51-7.46 (m, 2H), 7.38 (dd, J = 7.6, 1.5 Hz, 1H),
7.30-7.26 (m, 1H), 7.25-7.14 (m, 4H), 7.04 (dd, J = 7.5, 1.6
Hz, 1H), 6.84 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H),
3
1
1
3
1
9
119.9 (d, J = 18.6 Hz), 117.7 (d, J = 21.6 Hz), 116.5. F NMR
(376 MHz, CDCl ): δ -130.3 (dd, J = 9.5, 6.7 Hz, 1F). IR
(KBr): 3466, 3380, 3058, 1610, 1507, 1486, 1407, 1191, 1066,
3
1
3
1
3
.52 (brs, 2H). C{ H} NMR (100 MHz, CDCl ): δ 143.6,
-1
+
39.1, 136.0, 135.94, 135.86, 135.8, 130.5, 129.7, 129.2,
28.9, 128.4, 128.2, 127.7, 127.6, 125.6, 118.2, 115.4. IR
878, 765 cm . MS (EI, m/z, %): 221 (M , 100), 185 (82.36),
220 (48.17). HRMS (EI): calcd. for C12
Found: 221.0414.
9
H NFCl: 221.0408 (M);
(KBr): 3457, 3367, 3049, 1613, 1495, 1451, 1439, 1391, 746
-1
+
cm . MS (EI, m/z, %): 307 (M , 28.29), 167 (100), 137
20.12). HRMS (EI): calcd. for C18 : 307.0489 (M);
Found: 307.0500.
(
H
13NS
2
4-fluoro-5-nitro-[1,1'-biphenyl]-2-amine. According to GP1,
the residue was purified by flash chromatography on silica gel
(
eluent: ether/EtOAc = 30:1) to give target compound as a
3'-methyl-[1,1'-biphenyl]-2-amine.20 According to GP1, the
residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
yellow solid (1.876 g, yield = 81%). Mp: 136-139 C. H
NMR (400 MHz, CDCl ): δ 7.94 (d, J = 8.3 Hz, 1H), 7.49 (t, J
= 7.4 Hz, 2H), 7.44-7.38 (m, 3H), 6.49 (d, J = 12.9 Hz, 1H),
o
1
3
1
13
1
yellow liquid (1.629 g, yield = 89%). H NMR (400 MHz,
3
4.66 (brs, 2H). C{ H} NMR (100 MHz, CDCl ): δ 157.3 (d,
CDCl
.11 (m, 3H), 6.84-6.80 (m, 1H), 6.77 (d, J = 8.0 Hz, 1H), 3.76
brs, 2H), 2.40 (s, 3H).
3
): δ 7.34 (t, J = 7.5 Hz, 1H), 7.27-7.25 (m, 2H), 7.18-
J = 262.7 Hz), 151.1 (d, J = 12.2 Hz), 135.8, 129.4, 128.9,
128.5, 127.6 (d, J = 5.8 Hz), 122.8 (d, J = 2.3 Hz), 102.0,
7
(
1
9
101.8. F NMR (376 MHz, CDCl
3
): δ -116.0 (m, 1F). IR
(
KBr): 3492, 3357, 3045, 1628, 1577, 1567, 1487, 1305, 1243,
-1
+
3
',5'-bis(trifluoromethyl)-[1,1'-biphenyl]-2-amine. According
1112, 855, 747, 622 cm . MS (EI, m/z, %): 307 (M , 100),
202 (61.89), 185 (51.41). HRMS (EI): calcd. for C H FN O :
to GP1, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 30:1) to give target
compound as a white solid (2.532 g, yield = 83%). Mp: 38-40
1
2
9
2
2
232.0648 (M); Found: 232.0651.
o
1
2-isocyano-1,1'-biphenyl (2a).15a According to GP2, the
residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
C. H NMR (400 MHz, CDCl
3
): δ 7.98 (s, 2H), 7.88 (s, 1H),
.25 (td, J = 7.7, 1.5 Hz, 1H), 7.13 (dd, J = 7.6, 1.6 Hz, 1H),
.89 (td, J = 7.5, 1.1 Hz, 1H), 6.82 (dd, J = 8.0, 1.1 Hz, 1H),
7
6
3
1
1
3
1
1
.70 (brs, 2H). C{ H} NMR (100 MHz, CDCl
3
): δ 143.3,
green liquid (0.301 g, yield = 84%). H NMR (400 MHz,
41.8, 132.2 (q, J = 33.2 Hz), 130.4, 129.9, 129.3 (d, J = 3.7
3
CDCl ): δ 7.55-7.41 (m, 8H), 7.38 (td, J = 7.7, 2.1 Hz, 1H).
Hz), 124.3, 123.3 (q, J = 271.2 Hz), 121.0 (m), 119.2, 116.2.
1
9
4'-(tert-butyl)-2-isocyano-1,1'-biphenyl (2b).15a According to
GP2, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 30:1) to give target
F NMR (376 MHz, CDCl
3
): δ -62.83 (s, 6F). IR (KBr): 3481,
-1
3
386, 1621, 1484, 1452, 1413, 1258, 1114, 824, 753 cm . MS
+
(EI, m/z, %): 305 (M , 100), 216 (60.81), 284 (38.61). HRMS
1
(EI): calcd. for C14 NF : 305.0639 (M); Found: 305.0645.
H
9
6
compound as a green liquid (0.452 g, yield = 96%). H NMR
(400 MHz, CDCl
1.38 (s, 9H).
3
): δ 7.52-7.43 (m, 7H), 7.37-7.33 (m, 1H),
5
-methyl-[1,1'-biphenyl]-2-amine.15a According to GP1, the
residue was purified by flash chromatography on silica gel
eluent: ether/EtOAc = 30:1) to give target compound as a
2-isocyano-4'-methoxy-1,1'-biphenyl (2c).15a According to
GP2, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 30:1) to give target
(
1
yellow liquid (1.776 g, yield = 97%). H NMR (400 MHz,
CDCl ): δ 7.47-7.42 (m, 4H), 7.36-7.32 (m, 1H), 6.99-6.96 (m,
H), 6.70 (d, J = 7.9 Hz, 1H), 3.64 (brs, 2H), 2.28 (s, 3H).
3
1
2
compound as a pale green solid (0.328 g, yield = 78%). H
3
NMR (400 MHz, CDCl ): δ 7.48-7.40 (m, 5H), 7.35-7.31 (m,
5
-chloro-[1,1'-biphenyl]-2-amine.22 According to GP1, the
1H), 7.02 (dd, J = 8.7, 1.1 Hz, 2H), 3.87 (s, 3H).
residue was purified by flash chromatography on silica gel
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
(
2'-isocyano-[1,1'-biphenyl]-4-yl)(methyl)sulfane
(2d).15a
2H). 19F NMR (376 MHz, CDCl
J = 8.8 Hz, 1F).
3
): δ -108.8 (m, 1F), -109.7 (q,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
According to GP2, the residue was purified by flash
chromatography on silica gel (eluent: ether/EtOAc = 30:1) to
4-(2-isocyanophenyl)dibenzo[b,d]furan (2l).15a According to
GP2, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 30:1) to give target
compound as a white solid (0.462 g, yield = 86%). H NMR
3
(400 MHz, CDCl ): δ 8.04 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.7
give target compound as a white solid (0.418 g, yield = 81%).
1
3
H NMR (400 MHz, CDCl ): δ 7.51-7.31 (m, 8H), 2.54 (s, 3H).
-isocyano-1,1':4',1''-terphenyl (2e).15a According to GP2, the
residue was purified by flash chromatography on silica gel
eluent: ether/EtOAc = 30:1) to give target compound as a
1
2
(
Hz, 1H), 7.67 (d, J = 7.3 Hz, 1H), 7.60-7.53 (m, 4H), 7.51-
7.45 (m, 3H), 7.37 (t, J = 7.5 Hz, 1H).
1
white solid (0.413 g, yield = 81%). H NMR (400 MHz,
CDCl ): δ 7.72 (dd, J = 8.4, 1.9 Hz, 2H), 7.67 (dd, J = 7.2, 1.8
Hz, 2H), 7.61 (dd, J = 8.3, 1.9 Hz, 2H), 7.53-7.46 (m, 5H),
7.42-7.37 (m, 2H).
3
(2m).15a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4-(2-isocyanophenyl)dibenzo[b,d]thiophene
According to GP2, the residue was purified by flash
chromatography on silica gel (eluent: ether/EtOAc = 30:1) to
1
-(2'-isocyano-[1,1'-biphenyl]-4-yl)naphthalene
(2f).
give target compound as a white solid (0.467 g, yield = 82%).
1
According to GP2, the residue was purified by flash
chromatography on silica gel (eluent: ether/EtOAc = 30:1) to
give target compound as a white solid (0.537 g, yield = 88%).
3
H NMR (400 MHz, CDCl ): δ 8.25-8.20 (m, 2H), 7.82 (d, J =
7.3 Hz, 1H), 7.67 (dd, J = 7.5, 1.6 Hz, 1H), 7.63-7.45 (m, 7H).
o
1
Mp: 127-129 C. H NMR (400 MHz, CDCl
3
): δ 8.01 (d, J =
.3 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H),
.68-7.63 (m, 4H), 7.59-7.47 (m, 7H), 7.42 (t, J = 7.9 Hz, 1H).
1-(2-isocyanophenyl)thianthrene (2n). According to GP2, the
residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
8
7
13
1
o
1
C{ H} NMR (100 MHz, CDCl
3
): δ 166.6, 140.8, 139.5,
white solid (0.476 g, yield = 75%). Mp: 144-146 C. H NMR
(400 MHz, CDCl ): δ 8.25-8.19 (m, 2H), 7.84-7.79 (m, 1H),
7.68-7.66(m, 1H), 7.63-7.45 (m, 7H). C{ H} NMR (100
MHz, CDCl ): δ 166.6, 137.4, 137.2, 136.5, 135.9, 135.5,
138.5, 135.8, 133.8, 131.5, 130.6, 130.2, 129.6, 128.9, 128.3,
128.2, 128.0, 127.9, 127.0, 126.2, 125.9, 125.8, 125.4. IR
3
1
3
1
(KBr): 3029, 2117, 1591, 1516, 1480, 1442, 1393, 1205, 1017,
3
-1
8
1
05, 785 cm . MS (EI, m/z, %): 305 (M+, 100), 304 (93.87),
38 (46.11). HRMS (EI): calcd. for C23 15N: 305.1204 (M);
135.2, 131.1, 129.2, 129.1, 128.98, 128.96, 128.5, 127.9,
127.7, 127.3, 127.2. IR (KBr): 3063, 2124, 1487, 1450, 1436,
H
-1
+
Found: 2305.1198.
1391, 798, 764, 742, 722 cm . MS (EI, m/z, %): 317 (M ,
00), 285 (37.2), 283 (33.48). HRMS (EI): calcd. for
19 2
C H11NS : 317.0333 (M); Found: 317.0329.
1
2
-isocyano-4'-(methylsulfonyl)-1,1'-biphenyl
(2g).15a
According to GP2, the residue was purified by flash
chromatography on silica gel (eluent: ether/EtOAc = 2:1) to
2-isocyano-3'-methyl-1,1'-biphenyl (2o).15f According to GP2,
the residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1)to give target compound as a
give target compound as a white solid (0.410 g, yield = 80%).
1
3
H NMR (400 MHz, CDCl ): δ 8.07 (d, J = 8.5 Hz, 2H), 7.72
1
(d, J = 8.5 Hz, 2H), 7.55-7.42 (m, 4H), 3.13 (s, 3H).
green liquid (0.274 g, yield = 71%). H NMR (400 MHz,
CDCl
3H).
3
): δ 7.49-7.32 (m, 7H), 7.24 (d, J = 7.5 Hz, 1H), 2.43 (s,
methyl 2'-isocyano-[1,1'-biphenyl]-4-carboxylate (2h).15c
According to GP2, the residue was purified by flash
chromatography on silica gel (eluent: ether/EtOAc = 3:1) to
give target compound as a white solid (0.417 g, yield = 88%).
2-isocyano-3',5'-bis(trifluoromethyl)-1,1'-biphenyl
(2p).
According to GP2, the residue was purified by flash
chromatography on silica gel (eluent: ether/EtOAc = 30:1) to
give target compound as a gray solid (0.510 g, yield = 81%).
1
H NMR (400 MHz, CDCl
3
): δ 8.15 (d, J = 8.4 Hz, 2H), 7.59
(d, J = 8.4 Hz, 2H), 7.52-7.40 (m, 4H), 3.95 (s, 3H).
o
1
Mp: 88-91 C. H NMR (400 MHz, CDCl
3
): δ 7.98 (s, 3H),
(2i).15a
7.58-7.46 (m, 4H). C{ H} NMR (100 MHz, CDCl ): δ 168.4,
13
1
2-isocyano-4'-(trifluoromethyl)-1,1'-biphenyl
According to GP2, the residue was purified by flash
chromatography on silica gel (eluent: ether/EtOAc = 30:1) to
3
139.0, 135.7, 132.0 (q, J = 33.6 Hz), 130.3, 130.0, 129.8,
129.3 (q, J = 3.7 Hz), 128.1, 124.7, 123.1 (q, J = 271.2 Hz),
1
9
give target compound as a white solid (0.450 g, yield = 91%).
122.3 (m). F NMR (376 MHz, CDCl
3
): δ -62.9 (m, 6F). IR
1
H NMR (400 MHz, CDCl
3
): δ 7.75 (d, J = 8.1 Hz, 2H), 7.63
(KBr): 3060, 2121, 1383, 1281, 1180, 1122, 1058, 924, 904,
-1
+
(
d, J = 8.1 Hz, 2H), 7.54-7.49 (m, 2H), 7.44 (t, J = 7.2 Hz, 2H).
846, 766, 715, 706 cm . MS (EI, m/z, %): 315 (M , 100), 226
(73.78), 265 (52.16). HRMS (EI): calcd. for C17 NF
15.0483 (M); Found: 315.0480.
1
9
F NMR (376 MHz, CDCl
3
): δ -62.7 (s, 3F).
H
7
6
:
3
2
-isocyano-2'-methyl-1,1'-biphenyl (2j).23 According to GP2,
the residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
green liquid (0.186 g, yield = 67%). H NMR (400 MHz,
CDCl
3
2-isocyano-5-methyl-1,1'-biphenyl (2q).15a According to GP2,
the residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
1
1
3
): δ 7.49-7.27 (m, 7H), 7.17 (d, J = 7.3 Hz, 1H), 2.17 (s,
green liquid (0.358 g, yield = 90%). H NMR (400 MHz,
H).
CDCl
3
): δ 7.52-7.40 (m, 5H), 7.38 (d, J = 8.1 Hz, 1H), 7.23 (s,
1
H), 7.17 (d, J = 8.0 Hz, 1H), 2.42 (s, 3H).
2
,4-difluoro-2'-isocyano-1,1'-biphenyl (2k). According to GP2,
the residue was purified by flash chromatography on silica gel
eluent: ether/EtOAc = 30:1)to give target compound as a
5-chloro-2-isocyano-1,1'-biphenyl (2r).15c According to GP2,
the residue was purified by flash chromatography on silica gel
(eluent: ether/EtOAc = 30:1) to give target compound as a
green liquid (0.663 g, yield = 89%). H NMR (400 MHz,
3
CDCl ): δ 7.50-7.42 (m, 7H), 7.35 (dd, J = 8.5, 2.3 Hz, 1H).
(
1
brown solid (0.391 g, yield = 91%). H NMR (400 MHz,
CDCl ): δ 7.51-7.43 (m, 3H), 7.42-7.32 (m, 2H), 7.03-6.95 (m,
1
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
3
,5-difluoro-2-isocyano-1,1'-biphenyl (2s).15a According to
δ 165.0, 161.5, 151.4, 149.8, 142.0, 131.7, 130.8, 128.7, 128.3,
128.2, 124.3, 124.2, 123.5 (q, J = 283.6 Hz), 122.8 (q, J = 3.9
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
GP2, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 30:1) to give target
compound as a white solid (0.341 g, yield = 79%). H NMR
Hz), 122.3, 121.6, 68.3, 68.1 (q, J = 26.2 Hz), 54.9, 53.6, 35.1,
1
19
31.2. F NMR (376 MHz, CDCl
3
): δ -61.7 (s, 3F). IR (KBr):
(
400 MHz, CDCl
F NMR (376 MHz, CDCl
.5 Hz, 1F).
3
): δ 7.51-7.47 (m, 5H), 6.99-6.93 (m, 2H).
3075, 2967, 2951, 1765, 1478, 1460, 1350, 1262, 1189, 1171,
1
9
-1
3
): δ -105.0 (m, 1F), -111.7 (t, J =
1042, 1008, 942, 919, 768, 742, 728 cm . HRMS (ESI) for
+
8
C
24
H
24
O
3
N
2
F
3
(M+H ): Calcd: 445.1734; Found: 445.1725.
4
-chloro-5-fluoro-2-isocyano-1,1'-biphenyl (2t). According to
methyl
2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(8-
GP2, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 30:1) to give target
compound as a white solid (0.369 g, yield = 84%). Mp: 81-83
methoxyphenanthridin-6-yl)propanoate (3ac). According to
GP3, the residue was purified by flash chromatography on
silica gel to give target compound as a white solid (66.1 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
o
1
C. H NMR (400 MHz, CDCl
7.52-7.44 (m, 5H), 7.23 (d, J = 9.2 Hz, 1H). C{ H} NMR
100 MHz, CDCl ): δ 168.2, 157.8 (d, J = 254.6 Hz), 139.5 (d,
J = 7.6 Hz), 135.1, 129.8, 129.1, 128.8, 128.7, 120.7 (d, J =
3
): δ 7.57 (d, J = 6.7 Hz, 1H),
3
yield = 79%). Mp: 121-124 C. H NMR (400 MHz, CDCl ): δ
1
3
1
8.58 (d, J = 8.3 Hz, 1H), 8.50-8.45 (m, 1H), 8.10-8.04 (m, 1H),
(
3
7.72-7.63 (m, 2H), 7.50-7.45 (m, 2H), 4.49-4.35 (m, 2H), 4.09
1
3
1
(t, J = 9.6 Hz, 2H), 3.96 (s, 3H), 3.89 (s, 3H). C{ H} NMR
(100 MHz, CDCl ): δ 165.0, 161.5, 158.2, 150.3, 141.4, 130.8,
1
9
1
9.5 Hz), 118.4, 118.1. F NMR (376 MHz, CDCl
3
): δ -111.2
3
(dd, J = 9.2, 6.8 Hz, 1F). IR (KBr): 3038, 2126, 1564, 1481,
128.39, 128.35, 127.8, 125.8, 124.3, 124.2, 123.6 (q, J = 283.7
-1
1
446, 1392, 1268, 1080, 891, 780, 758, 711, 696, 515 cm .
Hz), 121.5, 121.3, 106.6 (q, J = 4.0 Hz), 68.4, 68.1 (q, J = 26.3
+
19
MS (EI, m/z, %): 231 (M , 100), 195 (44.77), 196 (41.88).
HRMS (EI): calcd. for C13 NFCl: 231.0251 (M); Found:
31.0242.
Hz), 55.4, 54.8, 53.7. F NMR (376 MHz, CDCl
3
): δ -61.4 (s,
H
7
3F). IR (KBr): 2950, 1756, 1660, 1621, 1573, 1531, 1484,
1462, 1446, 1364, 1249, 1227, 1190, 1036, 946, 834, 771, 742
2
-1
+
cm . HRMS (ESI) for
C
21
H
18
O
4
N
2
F
3
(M+H ): Calcd:
4-fluoro-2-isocyano-5-nitro-1,1'-biphenyl (2u). According to
GP2, the residue was purified by flash chromatography on
silica gel (eluent: ether/EtOAc = 30:1) to give target
compound as a yellow solid (0.208 g, yield = 43%). Mp: 115-
419.1213; Found: 419.1209.
methyl
2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(8-
(methylthio)phenanthridin-6-yl)propanoate (3ad). According
to GP3, the residue was purified by flash chromatography on
silica gel to give target compound as a yellow solid (77.3 mg,
o
1
1
1
1
1
18 C. H NMR (400 MHz, CDCl
3
): δ 8.17 (d, J = 7.6 Hz,
H), 7.54-7.45 (m, 6H). C{ H} NMR (100 MHz, CDCl ): δ
73.0, 154.2 (d, J = 267.8 Hz), 136.2 (d, J = 4.9 Hz), 133.8,
1
3
1
3
o
1
3
yield = 89%). Mp: 135-138 C. H NMR (400 MHz, CDCl ): δ
19
29.6, 129.1, 128.8, 128.1 (d, J = 2.2 Hz), 118.1, 117.9.
F
8.54 (d, J = 8.8 Hz, 1H), 8.49 (dd, J = 6.5, 3.3 Hz,1H), 8.11-
8.05 (m, 1H), 7.85 (s, 1H), 7.72-7.67 (m, 3H), 4.49-4.35 (m,
2H), 4.09 (t, J = 9.6 Hz, 2H), 3.96 (s, 3H), 2.55 (s, 3H).
NMR (376 MHz, CDCl
036, 2125, 1564, 1480, 1446, 1209, 890, 780, 711, 696 cm .
3
): δ -116.5 (m, 1F). IR (KBr): 3074,
-1
3
+
13
1
MS (EI, m/z, %): 242 (M , 48.05), 195 (100), 169 (74.73).
HRMS (EI): calcd. for C13
242.0494.
3
C{ H} NMR (100 MHz, CDCl ): δ 164.9, 161.4, 150.2,
H
7
N
2
O
2
F: 242.0492 (M); Found:
141.8, 138.5, 131.2, 130.8, 129.4, 128.5, 128.4, 125.0, 124.1,
123.4 (q, J = 283.7 Hz), 122.8, 121.7 (q, J = 4.0 Hz), 121.5,
1
9
6
8.4, 68.0 (q, J = 26.2 Hz), 54.8, 53.7, 15.3. F NMR (376
methyl
2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-
MHz, CDCl ): δ -61.5 (s, 3F). IR (KBr): 2956, 2923, 1763,
3
(phenanthridin-6-yl)propanoate (3aa). According to GP3, the
1657, 1565, 1460, 1434, 1354, 1265, 1207, 1186, 1169, 1039,
-1
residue was purified by flash chromatography on silica gel to
give target compound as a white solid (62.8 mg, yield = 81%).
Mp: 136-138 C. H NMR (400 MHz, CDCl
21 18 3 2 3
1016, 940, 759, 723 cm . HRMS (ESI) for C H O N F S
+
(M+H ): Calcd: 435.0985; Found: 435.0981.
o
1
3
): δ 8.69 (d, J =
8
.3 Hz, 1H), 8.57 (dd, J = 7.6, 2.1 Hz, 1H), 8.12-8.08 (m, 2H),
methyl 2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(8-
7.83 (t, J = 7.7 Hz, 1H), 7.75-7.70 (m, 2H), 7.65 (t, J = 7.7 Hz,
1H), 4.47-4.35 (m, 2H), 4.09 (t, J = 9.1 Hz, 2H), 3.95 (s, 3H).
phenylphenanthridin-6-yl)propanoate (3ae). According to
GP3, the residue was purified by flash chromatography on
silica gel to give target compound as a white solid (77.9 mg,
1
3
1
3
C{ H} NMR (100 MHz, CDCl ): δ 165.0, 161.3, 151.2,
o
1
1
3
6
42.1, 133.9, 130.8, 130.4, 128.8, 128.3, 126.9, 126.5 (q, J =
.7 Hz), 124.5, 124.2, 123.4 (q, J = 283.7 Hz), 122.6, 121.8,
3
yield = 84%). Mp: 135-138 C. H NMR (400 MHz, CDCl ): δ
8.73 (d, J = 8.6 Hz, 1H), 8.59-8.55 (m, 1H), 8.38 (s, 1H), 8.11
(t, J = 7.6 Hz, 2H), 7.77-7.66 (m, 4H), 7.51 (t, J = 7.5 Hz, 2H),
7.42 (t, J = 7.3 Hz, 1H), 4.46-4.29 (m, 2H), 4.12-4.00 (m, 2H),
1
9
8.4, 68.0 (q, J = 26.3 Hz), 54.8, 53.7. F NMR (376 MHz,
): δ -61.7 (s, 3F). IR (KBr): 2949, 1760, 1655, 1266,
CDCl
203, 1186, 1167, 1045, 1035, 1012, 934, 758, 725, 716 cm .
3
-1
13
1
1
3
3.97 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ 165.0, 161.4,
+
MS (EI, m/z, %): 388 (M , 1.93), 149 (100), 84 (25.22).
HRMS (EI): calcd. for C20 :388.1035 (M); Found:
88.1036.
151.3, 142.1, 139.9, 139.4, 132.9, 130.9, 129.5, 129.2, 128.8,
128.4, 128.0, 127.0, 125.0, 124.6 (q, J = 3.5 Hz), 124.1, 123.5
(q, J = 283.7 Hz), 123.2, 121.8, 68.4, 68.1 (q, J = 26.0 Hz),
15 2 3 3
H N O F
3
1
9
54.9, 53.8. F NMR (376 MHz, CDCl
3
): δ -61.6 (s, 3F). IR
methyl
2-(8-(tert-butyl)phenanthridin-6-yl)-2-(4,5-
(3ab).
(KBr): 3034, 1764, 1658, 1576, 1480, 1460, 1354, 1263, 1208,
-1
dihydrooxazol-2-yl)-3,3,3-trifluoropropanoate
According to GP3, the residue was purified by flash
chromatography on silica gel to give target compound as a
1189, 1013, 939, 758, 726, 698 cm . HRMS (ESI) for
+
C H O N F (M+H ): Calcd: 465.1421; Found: 465.1416.
26 20
3
2 3
o
1
white solid (70.2 mg, yield = 79%). Mp: 158-160 C. H NMR
400 MHz, CDCl ): δ 8.61 (d, J = 8.8 Hz, 1H), 8.56-8.52 (m,
H), 8.14 (s, 1H), 8.11-8.08 (m, 1H), 7.92 (d, J = 8.7 Hz, 1H),
.73-7.66 (m, 2H), 4.48-4.32 (m, 2H), 4.11 (t, J = 9.4 Hz, 2H),
methyl
2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(8-
(
3
(naphthalen-1-yl)phenanthridin-6-yl)propanoate (3af).
According to GP3, the residue was purified by flash
1
7
4
chromatography on silica gel to give target compound as a
13
1
o
1
.96 (s, 3H), 1.42 (s, 9H). C{ H} NMR (100 MHz, CDCl
3
):
white solid (68.9 mg, yield = 67%). Mp: 152-153 C. H NMR
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
(
400 MHz, CDCl
3
): δ 8.80 (d, J = 8.2 Hz, 1H), 8.64 (d, J = 6.0
MHz, CDCl
3
): δ -61.9 (s, 3F), -62.5 (s, 3F). IR (KBr): 2956,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hz, 1H), 8.23 (s, 1H), 8.16-8.12 (m, 1H), 8.00-7.92 (m, 3H),
7.83 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 5.4 Hz, 2H), 7.61-7.55
(m, 2H), 7.50-7.42 (m, 2H), 4.41-4.28 (m, 2H), 4.00-3.82 (m,
1759, 1665, 1436, 1365, 1336, 1296, 1252, 1211, 1190, 1172,
1144, 1120, 1085, 1038, 1010, 834, 762, 725 cm . HRMS
(ESI) for C21
457.0981.
-1
+
15 3 2 6
H O N F (M+H ): Calcd: 457.0981; Found:
1
3
1
2
1
1
1
2
3
H), 3.94 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ 164.9,
61.2, 151.3, 142.2, 139.5, 139.2, 133.8, 133.0, 132.7, 131.5,
30.9, 128.8, 128.48, 128.47, 128.3, 127.9 (q, J = 4.2 Hz),
27.3, 126.3, 126.0, 125.6, 125.5, 124.5, 124.2, 123.5 (q, J =
83.6 Hz), 122.6, 121.9, 68.5, 68.2 (q, J = 26.2 Hz), 54.7, 53.7.
F NMR (376 MHz, CDCl
953, 2924, 1756, 1662, 1353, 1247, 1209, 1185, 1042, 802,
methyl
2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(10-
methylphenanthridin-6-yl)propanoate (3aj). According to
GP3, the residue was purified by flash chromatography on
silica gel to give target compound as a yellow solid (24.9 mg,
1
9
3
): δ -61.6 (s, 3F). IR (KBr): 3059,
o
1
2
7
3
yield = 31%). Mp: 129-131 C. H NMR (400 MHz, CDCl ): δ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
8.80 (d, J = 8.6 Hz, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 8.00 (d,
J = 8.5 Hz, 1H), 7.75-7.67 (m, 3H), 7.56-7.52 (m, 1H), 4.46-
4.34 (m, 2H), 4.10-4.05 (m, 2H), 3.93 (s, 3H), 3.14 (s, 3H).
22 3 2 3
92, 779, 729 cm . HRMS (ESI) for C30H O N F (M+H ):
Calcd: 515.1577; Found: 515.1580.
1
3
1
methyl
2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(8-
(3ag).
3
C{ H} NMR (100 MHz, CDCl ): δ 165.2, 161.5, 151.9,
(methylsulfonyl)phenanthridin-6-yl)propanoate
143.2, 135.8, 134.7, 133.5, 131.2, 128.0, 127.3, 126.4, 126.2,
125.8, 125.4, 124.8 (q, J = 3.7 Hz), 123.4 (q, J = 284.2 Hz),
According to GP3, the residue was purified by flash
chromatography on silica gel to give target compound as a
1
9
68.4, 68.2 (q, J = 25.8 Hz), 54.8, 53.7, 27.1. F NMR (376
MHz, CDCl ): δ -61.5 (s, 3F). IR (KBr): 2958, 1761, 1660,
1458, 1438, 1353, 1265, 1192, 1172, 1028, 1012, 764, 727 cm
o
1
white solid (66.2 mg, yield = 71%). Mp: 197-198 C. H NMR
400 MHz, CDCl ): δ 8.83 (d, J = 8.8 Hz, 1H), 8.80 (s, 1H),
.59 (d, J = 8.0 Hz, 1H), 8.29 (dd, J = 8.8, 1.9 Hz, 1H), 8.16 (d,
J = 7.9 Hz, 1H), 7.84 (t, J = 7.1 Hz, 1H), 7.78 (t, J = 7.1 Hz,
H), 4.44 (t, J = 7.1 Hz, 2H), 4.22-4.04 (m, 2H), 4.00 (s, 3H),
3
-
(
8
3
1
+
18 3 2 3
. HRMS (ESI) for C21H O N F (M+H ): Calcd: 403.1264;
Found: 403.1260.
1
1
3
1
3.12 (s, 3H). C{ H} NMR (100 MHz, CDCl
151.3, 143.1, 138.6, 137.1, 131.1, 130.6, 129.2, 128.1 (q, J =
3
1
3
): δ 164.3, 160.6,
methyl
2-(8,10-difluorophenanthridin-6-yl)-2-(4,5-
(3ak).
dihydrooxazol-2-yl)-3,3,3-trifluoropropanoate
According to GP3, the residue was purified by flash
chromatography on silica gel to give target compound as a
yellow solid (39.9 mg, yield = 47%). Mp: 151-153 C. H
NMR (400 MHz, CDCl ): δ 8.91 (d, J = 7.9 Hz, 1H), 8.16-
.5 Hz), 127.2, 124.2, 124.0, 123.3 (q, J = 283.5 Hz), 123.0,
1
9
22.4, 68.8, 67.6 (q, J = 26.0 Hz), 54.8, 54.0, 44.6. F NMR
): δ -62.2 (s, 3F). IR (KBr): 3027, 2960,
927, 1758, 1663, 1434, 1359, 1308, 1247, 1189, 1151, 1099,
o
1
(376 MHz, CDCl
3
2
1
C
3
-1
040, 972, 755, 724, 565, 547, 500 cm . HRMS (ESI) for
8.11 (m, 1H), 7.81-7.72 (m, 2H), 7.65 (d, J = 10.0 Hz, 1H),
7.38 (ddd, J = 13.1, 8.2, 2.5 Hz, 1H), 4.51-4.38 (m, 2H), 4.10-
+
21
H
18
O
5
N
2
F
3
S (M+H ): Calcd: 467.0883; Found: 467.0895.
13
1
4
3
.05 (m, 2H), 3.96 (s, 3H). C{ H} NMR (100 MHz, CDCl ):
methyl
6-(2-(4,5-dihydrooxazol-2-yl)-1,1,1-trifluoro-3-
δ 164.6, 161.3 (dd, J = 256.7, 12.3 Hz), 161.0, 159.8 (dd, J =
247.5, 13.4 Hz), 149.9, 142.0, 131.0, 129.4 (d, J = 2.5 Hz),
129.0 (d, J = 1.4 Hz), 126.9 (dd, J = 9.6, 5.1 Hz), 126.0 (d, J =
24.6 Hz), 123.3 (q, J =284.0 Hz), 121.5 (dd, J = 4.7, 1.0 Hz),
120.6 (dd, J = 10.4, 2.7 Hz), 108.0 (dt, J = 23.1, 4.0 Hz), 107.3
(t, J = 27.3 Hz), 68.6, 68.1 (q, J = 25.6 Hz), 54.8, 53.9.
NMR (376 MHz, CDCl ): δ -61.3 (s, 3F), -103.9 (m, 1F), -
108.9 (q, J =9.6 Hz, 1F). IR (KBr): 2957, 1764, 1659, 1634,
1577, 1482, 1359, 1265, 1208, 1192, 1170, 1126, 1048, 1020,
methoxy-3-oxopropan-2-yl)phenanthridine-8-carboxylate
(3ah). According to GP3, the residue was purified by flash
chromatography on silica gel to give target compound as a
o
1
white solid (74.1 mg, yield = 83%). Mp: 186-188 C. H NMR
400 MHz, CDCl ): δ 8.89 (s, 1H), 8.71 (d, J = 8.7 Hz, 1H),
.58 (dd, J = 8.1, 1.6 Hz, 1H), 8.41 (dd, J = 8.7, 1.6 Hz, 1H),
.15-8.11 (m, 1H), 7.82-7.71 (m, 2H), 4.48-4.35 (m, 2H),
1
9
(
3
F
8
8
4
3
1
3
1
.19-4.04 (m, 2H), 4.00 (s, 3H), 3.99 (s, 3H). C{ H} NMR
): δ 166.3, 164.6, 161.0, 151.7, 142.9, 136.8,
-1
+
(100 MHz, CDCl
3
1011, 929, 767 cm . HRMS (ESI) for C20
Calcd: 425.0919; Found: 425.0915.
H
14
O
3
N
F
2 5
(M+H ):
1
1
31.0, 130.0, 129.9, 129.4 (q, J = 3.4 Hz), 128.7, 128.3, 124.0,
23.6, 123.3 (q, J = 283.4 Hz), 122.9, 122.4, 68.6, 67.7 (q, J =
1
9
26.3 Hz), 54.9, 53.9, 52.6. F NMR (376 MHz, CDCl
62.1 (s, 3F). IR (KBr): 2945, 1763, 1720, 1662, 1619, 1438,
1361, 1319, 1267, 1211, 1189, 1167, 1122, 1039, 1011, 938,
7
4
3
): δ -
methyl
2-(benzofuro[3,2-k]phenanthridin-6-yl)-2-(4,5-
(3al).
dihydrooxazol-2-yl)-3,3,3-trifluoropropanoate
According to GP3, the residue was purified by flash
chromatography on silica gel to give target compound as a
-1
+
57 cm . HRMS (ESI) for C22
47.1162; Found: 447.1160.
H
18
O
5
N
2
F
3
(M+H ): Calcd:
o
1
white solid (48.8 mg, yield = 51%). Mp: 198-199 C. H NMR
400 MHz, CDCl ): δ 9.68 (d, J = 8.2 Hz, 1H), 8.24-8.19 (m,
(
3
methyl
2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(8-
2H), 8.15-8.08 (m, 2H), 7.91-7.80 (m, 3H), 7.61 (t, J = 7.8 Hz,
1H), 7.47 (t, J = 7.5 Hz, 1H), 4.50-4.36 (m, 2H), 4.15-4.08 (m,
2H), 3.97 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ 165.1,
3
161.5, 156.8, 152.4, 151.1, 142.6, 130.6, 129.0, 128.7, 128.2,
127.0, 125.1, 124.1, 123.6, 123.5 (q, J = 283.8 Hz), 123.2,
122.4, 122.0, 121.4 (q, J = 3.7 Hz), 121.0, 119.3, 112.2, 68.5,
68.3 (q, J = 26.0 Hz), 54.9, 53.8. F NMR (376 MHz, CDCl ):
3
δ -61.5 (s, 3F). IR (KBr): 2957, 1746, 1660, 1628, 1456, 1434,
1360, 1275, 1244, 1217, 1184, 1102, 1043, 1032, 1002, 768,
742, 728 cm . HRMS (ESI) for C26
479.1213; Found: 479.1210.
(trifluoromethyl)phenanthridin-6-yl)propanoate (3ai).
13
1
According to GP3, the residue was purified by flash
chromatography on silica gel to give target compound as a
o
1
white solid (82.1 mg, yield = 90%). Mp: 157-158 C. H NMR
(400 MHz, CDCl ): δ 8.78 (d, J = 8.7 Hz, 1H), 8.58 (d, J = 8.3
Hz, 1H), 8.44 (s, 1H), 8.15 (dd, J = 7.7, 1.1 Hz, 1H), 8.02 (d, J
8.7 Hz, 1H), 7.85-7.74 (m, 2H), 4.45-4.34 (m, 2H), 4.12-
3
1
9
=
4
1
3
1
.05 (m, 2H), 3.98 (s, 3H). C{ H} NMR (100 MHz, CDCl
3
):
-1
+
δ 164.5, 161.0, 151.2, 142.7, 136.0, 131.0, 130.0, 129.0, 128.7
18 4 2 3
H O N F (M+H ): Calcd:
(q, J = 32.6 Hz), 126.1 (q, J = 3.2 Hz), 124.6 (m), 123.9, 123.8
(q, J =270.7Hz), 123.7, 123.31 (q, J = 283.6 Hz), 123.29,
1
9
1
22.2, 68.6, 67.8 (q, J = 26.3 Hz), 54.8, 53.9. F NMR (376
methyl 2-(benzo[4,5]thieno[3,2-k]phenanthridin-6-yl)-2-(4,5-
dihydrooxazol-2-yl)-3,3,3-trifluoropropanoate (3am).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
According to GP3, the residue was purified by flash
chromatography on silica gel to give target compound as a
Hz), 121.3 (q, J = 284.4 Hz), 121.2 (m), 119.7, 70.7 (q, J =
1
9
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
27.3 Hz), 68.8, 54.4, 54.0. F NMR (376 MHz, CDCl
3
): δ -
o
1
white solid (53.4 mg, yield = 54%). Mp: 192-195 C. H NMR
(400 MHz, CDCl ): δ 9.21 (dd, J = 8.5, 1.2 Hz, 1H), 8.47 (d, J
8.9 Hz, 1H), 8.37-8.32 (m, 1H), 8.27-8.23 (m, 2H), 8.09-
.04 (m, 1H), 7.95-7.88 (m, 1H), 7.87-7.82 (m, 1H), 7.65-7.56
m, 2H), 4.50-4.37 (m, 2H), 4.19-4.04 (m, 2H), 3.96 (s, 3H).
62.8 (s, 3F), -62.9 (s, 6F). IR (KBr): 2961, 1759, 1687, 1667,
-1
3
1383, 1285, 1250, 1179, 1118, 1038, 899, 845, 703, 683 cm .
+
=
8
HRMS (ESI) for C22
Found: 525.0851.
14 3 2 9
H O N F (M+H ): Calcd: 525.0855;
(
1
3
1
C{ H} NMR (100 MHz, CDCl
3
): δ 165.1, 161.5, 151.6,
methyl
2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(2-
1
1
1
2
43.1, 140.3, 137.4, 134.6, 134.2, 131.4, 130.8, 128.7, 128.6,
27.8, 125.25, 125.17, 124.3, 123.8, 123.5 (q, J = 284.1 Hz),
23.1 (q, J = 3.4 Hz), 122.4, 122.2, 120.5, 68.5, 68.3 (q, J =
methylphenanthridin-6-yl)propanoate (3aq). According to
GP3, the residue was purified by flash chromatography on
silica gel to give target compound as a white solid (57.9 mg,
o
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
3
yield = 72%). Mp: 111-113 C. H NMR (400 MHz, CDCl ): δ
6.0 Hz), 54.9, 53.8. F NMR (376 MHz, CDCl
3
): δ -61.5 (s,
3F). IR (KBr): 2956, 1747, 1660, 1576, 1434, 1347, 1302,
8.67 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H),
7.98 (d, J = 8.3 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.62 (t, J =
7.4 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 4.48-4.32 (m, 2H), 4.12-
-1
1244, 1214, 1187, 1153, 1037, 1002, 751, 729, 700 cm .
+
HRMS (ESI) for C26
Found: 495.0980.
18 3 2 3
H O N F S (M+H ): Calcd: 495.0985;
1
3
1
4.05 (m, 2H), 3.95 (s, 3H), 2.63 (s, 3H). C{ H} NMR (100
MHz, CDCl ): δ 165.1, 161.4, 150.2, 140.5, 138.4, 133.6,
3
methyl 2-(benzo[5,6][1,4]dithiino[2,3-k]phenanthridin-6-yl)-
-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoropropanoate (3an).
130.6, 130.5, 130.1, 126.7, 126.5 (q, J = 3.8 Hz), 124.5, 124.0,
123.5 (q, J = 284.0 Hz), 122.6, 121.3, 68.4, 68.3 (q, J = 26.0
2
1
9
According to GP3, the residue was purified by flash
Hz), 68.0 (q, J = 26.0 Hz), 54.8, 53.7, 22.1. F NMR (376
MHz, CDCl ): δ -61.8 (s, 3F). IR (KBr): 2954, 1759, 1662,
chromatography on silica gel to give target compound as a
3
o
1
pale yellow solid (72.6 mg, yield = 69%). Mp: 159-162 C. H
NMR (400 MHz, CDCl ): δ 9.51-9.45 (m, 1H), 8.16-8.11 (m,
1575, 1448, 1436, 1357, 1317, 1266, 1189, 1070, 1037, 1014,
-1
+
3
825, 770, 736 cm . HRMS (ESI) for C21
H
18
O
3
N
2
F
3
(M+H ):
1H), 7.99 (d, J = 8.7 Hz, 1H), 7.84-7.78 (m, 3H), 7.63-7.55 (m,
2H), 7.37-7.27 (m, 2H), 4.46-4.30 (m, 2H), 4.05 (d, J = 9.9 Hz,
Calcd: 403.1264; Found: 403.1258.
1
3
1
2
1
1
1
6
H), 3.92 (s, 3H). C{ H} NMR (100 MHz, CDCl
3
): δ 164.9,
methyl 2-(2-chlorophenanthridin-6-yl)-2-(4,5-dihydrooxazol-
2-yl)-3,3,3-trifluoropropanoate (3ar). According to GP3, the
residue was purified by flash chromatography on silica gel to
give target compound as a yellow solid (76.0 mg, yield =
61.3, 151.1, 143.4, 139.6, 137.0, 135.5, 135.0, 133.9, 130.6,
29.3, 129.2, 128.7, 128.5, 128.0, 127.95, 127.91, 127.3,
25.2 (q, J = 3.4 Hz), 125.1, 123.34, 123.31 (q, J = 284.1 Hz),
8.5, 68.0 (q, J = 26.0 Hz), 54.8, 53.8. F NMR (376 MHz,
): δ -61.4 (s, 3F). IR (KBr): 2952, 1752, 1667, 1578,
450, 1342, 1270, 1246, 1212, 1190, 1152, 1033, 1012, 765,
1
9
o
1
3
90%). Mp: 133-135 C. H NMR (400 MHz, CDCl ): δ 8.59 (d,
CDCl
3
J = 8.4 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 8.5 Hz,
1H), 8.03 (d, J = 8.3 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.71-
7.65 (m, 2H), 4.49-4.35 (m, 2H), 4.08 (t, J = 9.1 Hz, 2H), 3.94
1
7
5
-1
+
32 cm . HRMS (ESI) for C26
27.0705; Found: 527.0701.
18 3 2 3 2
H O N F S (M+H ): Calcd:
1
3
1
3
(s, 3H). C{ H} NMR (100 MHz, CDCl ): δ 164.8, 161.2,
151.5, 140.5, 134.4, 132.9, 132.3, 130.7, 129.4, 127.6, 126.6
methyl
2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(9-
(q, J = 3.7 Hz), 125.3, 124.7, 123.3 (q, J = 284.0 Hz), 122.7,
1
9
methylphenanthridin-6-yl)propanoate (3ao). According to
GP3, the residue was purified by flash chromatography on
silica gel to give target compound as a white solid (42.6 mg,
121.5, 68.5, 67.9 (q, J = 26.3 Hz), 54.8, 53.8. F NMR (376
MHz, CDCl ): δ -61.7 (s, 3F). IR (KBr): 2957, 1759, 1664,
1604, 1489, 1445, 1435, 1355, 1317, 1248, 1208, 1186, 1036,
3
o
1
-1
yield = 53%). Mp: 137-140 C. H NMR (400 MHz, CDCl
3
): δ
926, 854, 831, 766 cm . HRMS (ESI) for C20
H
15
O
3
N
2
ClF
3
+
8
7
1
2
.55 (dd, J = 7.7, 2.0 Hz, 1H), 8.46 (s, 1H), 8.10-8.06 (m, 1H),
.98 (d, J = 8.7 Hz, 1H), 7.74-7.65 (m, 2H), 7.46 (dd, J = 8.7,
(M+H ): Calcd: 423.0718; Found: 423.0712.
Hz, 1H), 4.48-4.34 (m, 2H), 4.12-4.05 (m, 2H), 3.95 (s, 3H),
methyl
2-(2,4-difluorophenanthridin-6-yl)-2-(4,5-
(3as).
13
1
3
.63 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ 165.1, 161.4,
dihydrooxazol-2-yl)-3,3,3-trifluoropropanoate
151.1, 142.3, 140.9, 134.2, 130.8, 128.7, 128.6, 128.0, 126.4
According to GP3, the residue was purified by flash
(q, J = 3.8 Hz), 124.1, 123.5 (q, J = 284.6 Hz), 122.6, 122.2,
chromatography on silica gel to give target compound as a
1
9
o
1
121.8, 68.4, 68.0 (q, J = 26.3 Hz), 54.8, 53.7, 22.1. F NMR
376 MHz, CDCl ): δ -61.8 (s, 3F). IR (KBr): 2956, 1759,
655, 1622, 1575, 1459, 1438, 1357, 1266, 1250, 1183, 1035,
white solid (53.4mg, yield = 63%). Mp: 157-160 C. H NMR
(400 MHz, CDCl ): δ 8.52 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.5
(
3
3
1
1
3
Hz, 1H), 7.97 (dt, J = 9.8, 2.1 Hz, 1H), 7.90-7.84 (m, 1H),
7.73 (ddd, J = 8.4, 7.1, 1.1 Hz, 1H), 7.23 (td, J = 9.1, 2.6 Hz,
1H), 4.53-4.38 (m, 2H), 4.08 (t, J = 9.6 Hz, 2H), 3.97 (s, 3H).
-1
+
007, 932, 761, 728 cm . MS (EI, m/z, %): 402 (M , 100),
43 (70.99), 402 (70.3). HRMS (EI): calcd. for
1
3
1
C
21
H
17
N
2
O
3
F
3
:402.1191 (M); Found: 402.1189.
C{ H} NMR (100 MHz, CDCl
3
): δ 164.8, 161.5 (dd, J =
2
48.5, 11.9 Hz), 161.2, 159.3 (dd, J = 259.2, 13.5 Hz), 150.9,
methyl 2-(7,9-bis(trifluoromethyl)phenanthridin-6-yl)-2-(4,5-
dihydrooxazol-2-yl)-3,3,3-trifluoropropanoate (3ap).
According to GP3, the residue was purified by flash
132.9 (dd, J = 4.7, 3.0 Hz), 131.0, 129.2 (dd, J = 10.8, 2.2 Hz),
128.2, 127.0 (dt, J = 6.4, 3.2 Hz), 126.8 (d, J = 2.2 Hz), 125.0,
123.3 (q, J = 283.7 Hz), 123.1, 104.5 (dd, J = 28.3, 22.6 Hz),
chromatography on silica gel to give target compound as a
102.7 (dd, J = 23.3, 4.7 Hz), 68.6, 68.2 (q, J = 26.9 Hz), 54.8,
o
1
19
white solid (95.4 mg, yield = 91%). Mp: 64-67 C. H NMR
400 MHz, CDCl ): δ 7.86-7.79 (m, 2H), 7.51-7.45 (m, 1H),
.40-7.34 (m, 2H), 7.01 (d, J = 7.9 Hz, 1H), 4.39-4.24 (m, 2H),
53.8. F NMR (376 MHz, CDCl
3
): δ -61.4 (s, 3F), -107.0 (q, J
(
3
= 8.9 Hz, 1F), -117.6 (m, 1F). IR (KBr): 2959, 1762, 1666,
1630, 1586, 1530, 1497, 1442, 1354, 1257, 1185, 1134, 1091,
7
3
.98-3.83 (m, 2H), 3.75 (s, 3H). 13C{ H} NMR (100 MHz,
): δ 161.9, 158.8, 145.4, 140.5, 131.4 (q, J = 33.2 Hz),
31.1, 130.3, 130.0, 129.5, 129.4, 126.7, 123.3 (q, J = 271.0
1
1033, 1015, 1000, 927, 767 cm . HRMS (ESI) for
-1
+
CDCl
1
3
C
20
H
14
O
3
N
2
F
5
(M+H ): Calcd: 425.0919; Found: 425.0914.
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The Journal of Organic Chemistry
methyl
2-(3-chloro-2-fluorophenanthridin-6-yl)-2-(4,5-
(3at).
5H), 4.68-4.58 (m, 1H), 4.26 (t, J = 8.9 Hz, 1H), 4.16 (t, J =
8.0 Hz, 1H), 3.93 (s, 3H), 3.22 (dd, J = 13.7, 4.8 Hz, 1H), 2.78
(dd, J = 13.7, 9.0 Hz, 1H). C{ H} NMR (100 MHz, CDCl ):
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
dihydrooxazol-2-yl)-3,3,3-trifluoropropanoate
According to GP3, the residue was purified by flash
chromatography on silica gel to give target compound as a
1
3
1
δ 164.9, 160.7, 151.3, 142.2, 137.4, 134.0, 130.8, 130.4, 129.4,
128.8, 128.6, 128.3, 126.82, 126.76 (q, J = 3.9 Hz), 126.6,
124.5, 124.3, 123.5 (q, J = 283.5 Hz), 122.6, 121.8, 72.4, 68.1
o
1
pale yellow solid (80.1 mg, yield = 91%). Mp: 189-190 C. H
NMR (400 MHz, CDCl ): δ 8.50 (d, J = 8.3 Hz, 1H), 8.24 (d, J
10.2 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 8.10 (d, J = 8.4 Hz,
H), 7.86 (t, J = 7.3 Hz, 1H), 7.69 (t, J = 8.2 Hz, 1H), 4.49-
3
1
9
=
3
(q, J = 27.3 Hz), 67.9, 53.7, 40.8. F NMR (376 MHz, CDCl ):
1
4
δ -61.7 (s, 3F). IR (film): 3063, 2952, 2927, 1759, 1661, 1576,
1
3
1
-1
.36 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 3H). C{ H} NMR
): δ 164.7, 161.1, 157.4 (d, J = 251.6 Hz),
51.9 (d, J = 3.1 Hz), 139.0 (d, J = 2.2 Hz), 133.0 (d, J = 4.1
1454, 1445, 1350, 1033, 1013, 909, 761, 727, 700 cm . MS
+
(100 MHz, CDCl
3
(EI, m/z, %): 478 (M , 3.72), 91 (100), 149 (80.93). HRMS
1
(EI): calcd. for C27
Isomer 2: colorless oil. H NMR (400 MHz, CDCl
H
21
N
2
1
O
3
F
3
: 478.1504 (M); Found: 478.1500.
): δ 8.68 (d,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz), 132.5, 130.9, 127.8, 126.8 (q, J = 3.5 Hz), 124.5, 124.3 (d,
J = 8.0 Hz), 123.3 (q, J = 283.8 Hz), 123.1 (d, J = 20.4 Hz),
122.8, 108.1 (d, J = 23.5 Hz), 68.6, 67.8 (q, J = 26.2 Hz), 54.8,
3
J = 8.2 Hz, 1H), 8.59-8.54 (m, 1H), 8.12-8.07 (m, 1H), 7.93 (d,
J = 8.6 Hz, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.76-7.68 (m, 2H),
7.55-7.49 (m, 1H), 7.37-7.23 (m, 5H), 4.67-4.58 (m, 1H), 4.34
1
9
53.9. F NMR (376 MHz, CDCl
3
): δ -61.7 (s, 3F), -113.4 (dd,
J = 10.1, 7.4 Hz, 1F). IR (KBr): 2952, 1762, 1665, 1488, 1450,
(t, J = 9.0 Hz, 1H), 4.08 (t, J = 8.0 Hz, 1H), 3.95 (s, 3H), 3.20
-1
13
1
357, 1256, 1184, 1166, 1057, 1035, 1010, 957, 884, 767 cm .
(dd, J = 13.8, 4.8 Hz, 1H), 2.92 (dd, J = 13.8, 8.3 Hz, 1H).
NMR (100 MHz, CDCl
133.9, 130.8, 130.4, 129.7, 128.8, 128.6, 128.3, 126.8, 126.7,
24.5, 124.2, 123.4 (q, J = 283.5 Hz), 122.6, 121.8, 72.1, 68.0
C
+
HRMS (ESI) for C20
Found: 441.0624.
H
14
O
3
N
2
ClF
4
(M+H ): Calcd: 441.0624;
3
): δ 165.0, 160.7, 151.2, 142.2, 137.2,
1
1
9
methyl 2-(4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-2-(3-fluoro-
-nitrophenanthridin-6-yl)propanoate (3au). According to
(q, J = 27.3 Hz), 67.7, 53.7, 40.5. F NMR (376 MHz, CDCl3):
δ -61.7 (s, 3F). IR (film): 3028, 2954, 2926, 1760, 1661, 1576,
1454, 1445, 1350, 1266, 1074, 1047, 1014, 909, 761, 727, 701
cm . MS (EI, m/z, %): 478 (M , 47.11), 387 (100), 91 (54.68).
HRMS (EI): calcd. for C H N O F : 478.1504 (M); Found:
2
GP3, the residue was purified by flash chromatography on
silica gel to give target compound as a yellow solid (65.0mg,
-1
+
o
1
yield = 72%). Mp: 159-162 C. H NMR (400 MHz, CDCl
3
): δ
.30 (d, J = 7.5 Hz, 1H), 8.65 (d, J = 8.3Hz, 1H), 8.16 (d, J =
.5 Hz, 1H), 7.99-7.94 (m, 2H), 7.75 (t, J = 7.8 Hz, 1H), 4.51-
2
7
21
2
3 3
9
8
4
478.1511.
1
3
1
.39 (m, 2H), 4.07 (t, J = 9.8 Hz, 2H), 3.93 (s, 3H). C{ H}
): δ 164.4, 160.8, 156.5, 155.9 (d, J =
63.0 Hz), 145.1 (d, J = 11.5 Hz), 137.4 (d, J = 10.0 Hz),
methyl 3,3,3-trifluoro-2-((R)-4-isobutyl-4,5-dihydrooxazol-2-
yl)-2-(phenanthridin-6-yl)propanoate (3da). According to
GP3, the residue was purified by flash chromatography on
NMR (100 MHz, CDCl
3
2
1
2
1
33.3, 132.1, 128.4, 127.2 (q, J = 3.0 Hz), 124.7, 123.1(q, J =
84.1 Hz), 122.8, 121.3 (d, J = 1.7 Hz), 120.7 (d, J = 2.9 Hz),
18.6 (d, J = 20.1 Hz), 68.7, 67.8 (q, J = 26.3 Hz), 54.8, 54.0.
silica gel to give target compound as a colorless oil (64.8 mg,
1
yield = 73%). H NMR (400 MHz, CDCl
3
): δ 8.68 (d, J = 8.4
Hz, 1H), 8.59-8.54 (m, 1H), 8.16-8.07 (m, 2H), 7.83 (t, J = 7.7
Hz, 1H), 7.76-7.68 (m, 2H), 7.67-7.60 (m, 1H), 7.37-7.23 (m,
5H), 4.50-4.30(m, 2H), 4.06-3.93 (m, 4H), 1.80-1.65 (m, 2H),
19
3
F NMR (376 MHz, CDCl ): δ -61.5 (s, 3F), -118.8 (dd, J =
11.1, 7.5 Hz, 1F). IR (KBr): 2956, 2920, 1759, 1663, 1627,
1584, 1544, 1523, 1452, 1344, 1247, 1217, 1194, 1154, 1039,
1
3
1
1.50-1.36 (m, 1H), 0.99-0.90 (m, 6H). C{ H} NMR (100
MHz, CDCl ): δ 165.2, 165.0, 159.8, 159.7, 151.4, 151.3,
142.20, 142.15, 134.0, 133.9, 130.9, 130.8, 130.4, 128.7,
28.2, 127.0 (q, J = 3.9 Hz), 126.71, 126.66, 126.62, 124.6,
-1
+
7
4
58 cm . HRMS (ESI) for C20
52.0864; Found: 452.0859.
H
14
O
5
N
3
F
4
(M+H ): Calcd:
3
1
methyl
2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3,3,3-
124.5, 124.3, 124.2, 123.49 (q, J = 283.7 Hz), 123.46 (q, J =
283.6 Hz), 122.6, 122.5, 121.8, 73.8, 73.7, 68.2 (q, J = 26.1
Hz), 67.9 (q, J = 26.3 Hz), 65.3, 65.2, 44.7, 25.4, 25.3, 23.0,
trifluoro-2-(phenanthridin-6-yl)propanoate (3ba). According
to GP3, the residue was purified by flash chromatography on
silica gel to give target compound as a white solid (62.5 mg,
19
22.9, 22.5, 22.4. F NMR (376 MHz, CDCl ): δ -61.5 (s,
3
o
1
yield = 75%). Mp: 139-142 C. H NMR (400 MHz, CDCl
3
): δ
1.5F), -61.8 (s, 1.5F). IR (film): 3026, 2990, 1691, 1656, 1582,
-1
8
.68 (d, J = 8.3 Hz, 1H), 8.58-8.54 (m, 1H), 8.16 (d, J = 8.5
1526, 1447, 1399, 1300, 1287, 1160, 823, 758, 742, 508 cm .
+
Hz, 1H), 8.12-8.08 (m, 1H), 7.86-7.80 (m, 1H), 7.76-7.67 (m,
2H), 7.66-7.60 (m, 1H), 4.08-4.00 (m, 2H), 3.96 (s, 3H), 1.41
HRMS (ESI) for C H O N F (M+H ): Calcd: 445.1734;
2
4
24
3
2 3
Found: 445.1731.
1
3
1
(
1
1
s, 3H), 1.38 (s, 3H). C{ H} NMR (100 MHz, CDCl
3
): δ
65.0, 158.3, 151.4, 142.2, 134.0, 130.8, 130.4, 128.7, 128.3,
26.9 (q, J = 3.7 Hz), 126.6, 124.5, 124.2, 123.5 (q, J = 283.6
methyl 2-((S)-4-((S)-sec-butyl)-4,5-dihydrooxazol-2-yl)-3,3,3-
trifluoro-2-(phenanthridin-6-yl)propanoate (3ea). According
to GP3, the residue was purified by flash chromatography on
Hz), 122.6, 121.8, 79.7, 68.2, 68.0 (q, J = 26.2 Hz), 53.6, 54.0,
1
9
2
7.62, 27.58. F NMR (376 MHz, CDCl
3
): δ -61.6 (s, 3F). IR
silica gel to give target compound as a colorless oil (63.1 mg,
1
(KBr): 2972, 1762, 1663, 1461, 1350, 1291, 1247, 1217, 1192,
yield = 71%). H NMR (400 MHz, CDCl
3
): δ 8.68 (d, J = 8.3
-1
1
038, 1013, 764, 729 cm . HRMS (ESI) for C22
H
20
O
3
N
2
F
3
Hz, 1H), 8.56 (d, J = 8.5 Hz, 1H), 8.17-8.07 (m, 2H), 7.83 (t, J
= 7.6 Hz, 1H), 7.76-7.68 (m, 2H), 7.66-7.59 (m, 1H), 4.42-
4.25 (m, 2H), 4.20-4.08 (m, 1H), 3.95 (s, 1.5H), 3.92 (s, 1.5H),
1.88-1.75 (m, 1H), 1.58-1.43 (m, 1H), 1.30-1.10 (m, 1H),
+
(M+H ): Calcd: 417.1421; Found: 417.1417.
methyl 2-((S)-4-benzyl-4,5-dihydrooxazol-2-yl)-3,3,3-trifluoro-
-(phenanthridin-6-yl)propanoate (3ca). According to GP3,
1
3
1
2
0.97-0.87 (m, 6H). C{ H} NMR (100 MHz, CDCl ): δ 165.1,
3
the residue was purified by flash chromatography on silica gel
to give target compound (77.5 mg, yield = 81%). Isomer 1:
yellow oil. H NMR (400 MHz, CDCl
165.0, 159.8, 159.6, 151.4, 142.20, 142.16, 133.93, 133.86,
130.9, 130.8, 130.38, 130.35, 128.7, 128.3, 128.2, 127.3 (q, J
= 4.0 Hz), 126.8 (q, J = 3.6 Hz), 126.7, 124.5, 124.25, 124.20,
123.5 (q, J = 284.4 Hz), 122.6, 122.5, 121.78, 121.77, 71.1,
71.0, 70.00, 69.98, 67.9 (q, J = 26.0 Hz), 67.8 (q, J = 26.5 Hz),
1
3
): δ 8.69 (d, J = 8.3 Hz,
1
1
H), 8.60-8.55 (m, 1H), 8.15-8.08 (m, 2H), 7.84 (t, J = 7.7 Hz,
H), 7.77-7.69 (m, 2H), 7.63 (t, J = 7.8 Hz, 1H), 7.31-7.18 (m,
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The Journal of Organic Chemistry
Page 12 of 14
5
3.6, 53.5, 38.6, 38.5, 26.2, 26.1, 14.3, 14.2, 11.7, 11.6. 19F
Notes
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (376 MHz, CDCl
(film): 3075, 2969, 2901, 1750, 1668, 1653, 1576, 1456, 1350,
): δ -61.6 (s, 1.5F), -61.7 (s, 1.5F). IR
3
The authors declare no competing financial interest.
-1
+
1250, 1045, 906, 760, 726 cm . MS (EI, m/z, %): 444 (M ,
24 3 2 3
2.59), 385 (100), 375 (54.46). HRMS (ESI) for C24H O N F
ACKNOWLEDGMENT
1
Financial support from Natural Science Foundation of
Shandong Province, China (ZR2016BQ31, ZR2016HM44,
ZR2017ZC0529), National Natural Science Foundation of
China (No. 21737004, 21672239, 21421002), and University
of Jinan is greatly appreciated.
+
(M+H ): Calcd: 445.1734; Found: 445.1730.
methyl 3,3,3-trifluoro-2-(phenanthridin-6-yl)-2-((R)-4-phenyl-
,5-dihydrooxazol-2-yl)propanoate (3fa). According to GP3,
4
the residue was purified by flash chromatography on silica gel
to give target compound as a colorless oil (66.8 mg, yield =
72%). H NMR (400 MHz, CDCl
8.60-8.54 (m, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.16-8.11 (m, 1H),
7.87-7.79 (m, 1H), 7.78-7.68 (m, 2H), 7.67-7.57 (m, 1H),
REFERENCES
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
): δ 8.68 (t, J = 7.8 Hz, 1H),
3
(
1) Huan, F.; Chen, Q.-Y.; Guo, Y. Visible Light-Induced
Photoredox Construction of Trifluoromethylated Quaternary
Carbon Centers from Trifluoromethylated Tertiary Bromides.
J. Org. Chem. 2016, 81, 7051-7063.
7
4
.44-7.27 (m, 5H), 5.49-5.42 (m, 1H), 4.88-4.74 (m, 1H),
1
3
1
.38-4.25 (m, 1H), 4.00 (s, 1.5H), 3.99 (s, 1.5H). C{ H}
): δ 165.1, 161.7, 161.6, 151.3, 151.2,
42.1, 141.41, 141.39, 134.0, 133.9, 130.8, 130.7, 130.45,
(2) (a) Uneyama, K. Organofluorine Chemistry, Blackwell,
Oxford: UK, 2006. (b) Ojima, I. Fluorine in Medicinal
Chemistry and Chemical Biology, Wiley-Blackwell,
Chichester, 2009.
NMR (100 MHz, CDCl
3
1
1
1
1
1
2
30.39, 128.79, 128.75, 128.68, 128.32, 128.29, 127.74,
27.71, 126.9, 126.8 (q, J = 6.4 Hz), 126.7, 124.42, 124.37,
23.49 (q, J = 283.8 Hz), 123.47 (q, J = 283.8 Hz), 122.6,
21.84, 121.79, 121.77, 75.67, 75.65, 70.0, 69.7, 68.4 (q, J =
6.4 Hz), 68.2 (q, J = 26.2 Hz), 53.74, 53.70. F NMR (376
): δ -61.2 (s, 1.5F), -61.4 (s, 1.5F). IR (film):
3023, 2920, 1734, 1614, 1482, 1454, 1396, 1295, 1158, 1105,
(
3) Todoroki, Y.; Hirai, N.; Koshimizu, K. 8’,8’-Difluoro- and
8’,8’,8’-Trifluoroabscisic Acids as Highly Potent, Long-
Lasting Analogues of Abscisic Acid. Phytochemistry 1995,
3
8, 561-568.
19
(
4) (a) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; Pozo, C.;
Sorochinsky, A. E.; 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. (b) Zhang, C.-P.;
Chen, Q.-Y.; Guo, Y.; Xiao, J.-C.; Gu, Y.-C.
Difluoromethylation and Trifluoromethylation Reagents
Derived from Tetrafluoroethane β-Sultone: Synthesis,
Reactivity and Applications. Coord. Chem. Rev. 2014, 261,
MHz, CDCl
3
-1
+
1
2
006, 833, 755, 745, 702 cm . MS (EI, m/z, %): 444 (M ,
2.95), 301 (100), 104 (29.92). HRMS (EI): calcd. for
26 19 2 3 3
C H N O F : 464.1348 (M); Found: 464.1339.
methyl 3,3,3-trifluoro-2-((S)-4-isopropyl-4,5-dihydrooxazol-2-
yl)-2-(phenanthridin-6-yl)propanoate (3ga). According to
GP3, the residue was purified by flash chromatography on
silica gel to give target compound as a colorless oil (62.8 mg,
yield = 73%). H NMR (400 MHz, CDCl
2
8-72. (c) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly,
D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal
Chemistry. J. Med. Chem. 2015, 58, 8315-8359. d) Zhou, Y.;
Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.;
Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of
Fluorine-Containing Pharmaceuticals, Compounds Currently
in Phase II–III Clinical Trials of Major Pharmaceutical
Companies: New Structural Trends and Therapeutic Areas.
Chem. Rev. 2016, 116, 422-518.
1
3
): δ 8.68 (d, J = 8.4
Hz, 1H), 8.59-8.54 (m, 1H), 8.18-8.07 (m, 2H), 7.83 (t, J = 7.7
Hz, 1H), 7.76-7.68 (m, 2H), 7.62 (t, J = 7.8 Hz, 1H), 4.44-4.29
(m, 1H), 4.21-4.08 (m, 2H), 3.95 (s, 1.5H), 3.92 (s, 1.5H),
1
3
1
2
.02-1.87 (m, 1H), 1.03-0.91 (m, 6H). C{ H} NMR (100
): δ 165.2, 165.0, 160.0, 159.7, 151.4, 142.22,
42.17, 134.0, 133.9, 130.9, 130.8, 130.38, 130.35, 128.7,
28.3, 128.2, 127.0 (q, J = 4.2 Hz), 126.8 (q, J = 3.8 Hz),
26.7, 124.5, 124.3, 124.2, 123.49 (q, J =283.6 Hz), 123.48 (q,
MHz, CDCl
3
(5) (a) Newman, D. J.; Cragg, G. M. Natural Products as Sources
1
1
1
of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79,
6
Natural Products in Drug Discovery. J. Med. Chem. 2016, 59,
9295-9304.
29-661. (b) DeCorte, B. L. Underexplored Opportunities for
J =283.6 Hz), 122.6, 122.5, 121.79, 121.78, 72.5, 72.4, 70.64,
0.61, 68.3 (q, J = 26.3 Hz), 67.9 (q, J = 26.4 Hz), 53.6, 53.5,
7
(6) (a) Quasdorf, K. W.; Overman, L. E. Catalytic
enantioselective synthesis of quaternary carbon stereocentres.
Nature 2014, 516, 181-191. (b) Zeng, X.-P.; Cao, Z.-Y.;
Wang, Y.-H.; Zhou, F.; Zhou, J. Catalytic Enantioselective
Desymmetrization Reactions to All-Carbon Quaternary
Stereocenters. Chem. Rev. 2016, 116, 7330-7396. (c) Feng, J.;
Holmes, M.; Krische, M. J. Acyclic Quaternary Carbon
Stereocenters via Enantioselective Transition Metal Catalysis.
Chem. Rev. 2017, 117, 12564-12580.
1
9
32.4, 32.3, 18.9, 18.8, 18.1, 18.0. F NMR (376 MHz, CDCl
δ -61.6 (s, 1.5F), -61.7 (s, 1.5F). IR (film): 3074, 2959, 1759,
1664, 1349, 1266, 1213, 1192, 1040, 1016, 952, 762, 727 cm .
HRMS (ESI) for C23
Found: 431.1574.
3
):
-1
+
22 3 2 3
H O N F : (M+H ): Calcd: 431.1577;
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
(7) (a) Kawai, H.; Okusu, S.; Tokunaga, E.; Sato, H.; Shiro, M.;
Shibata, N. Organocatalytic Asymmetric Synthesis of
Trifluoromethyl-substituted
Enantioselective Conjugate Cyanation of β-Aryl-β-
trifluoromethyl-disubstituted Enones. Angew. Chem. Int. Ed.
2
W.-B.; Han, L.; Jia, Y.-X. Highly Enantioselective
Construction of Trifluoromethylated All-Carbon Quaternary
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AUTHOR INFORMATION
Corresponding Author
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*
*
E-mail: chm_wangwg@ujn.edu.cn
E-mail: yguo@sioc.ac.cn
E-mail: chenqy@sioc.ac.cn
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