Palladium-catalyzed tandem cyclization of fluorinated imidoyl chlorides with 2-bromophenylboronic acid: Synthesis of 6-fluoroalkyl-phenanthridines

Article abstract of DOI:10.1016/j.tet.2019.01.058

An efficient method has been developed to synthesize 6-fluoroalkyl-phenanthridines via the palladium-catalyzed tandem cyclization of fluorinated imidoyl chlorides with 2-bromophenylboronic acid. This methodology facilitates the rapid synthesis of 6-fluoroalkyl-phenanthridines through dual C–C bond formation in an oxidant-free one-pot manner.

Full text of DOI:10.1016/j.tet.2019.01.058

Accepted Manuscript
Palladium-catalyzed tandem cyclization of fluorinated imidoyl chlorides with 2-
bromophenylboronic acid: Synthesis of 6-fluoroalkyl-Phenanthridines
Yinwei Bao, Zhuo Wang, Chen Chen, Bolin Zhu, Yuebo Wang, Jinghui Zhao, Jinyu
Gong, Mengya Han, Chang Liu
PII:
S0040-4020(19)30112-7
https://doi.org/10.1016/j.tet.2019.01.058
TET 30110
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 December 2018
Revised Date: 20 January 2019
Accepted Date: 25 January 2019
Please cite this article as: Bao Y, Wang Z, Chen C, Zhu B, Wang Y, Zhao J, Gong J, Han M, Liu C,
Palladium-catalyzed tandem cyclization of fluorinated imidoyl chlorides with 2- bromophenylboronic
acid: Synthesis of 6-fluoroalkyl-Phenanthridines, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.01.058.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Palladium-Catalyzed Tandem Cyclization of
Fluorinated Imidoyl Chlorides with 2-
Bromophenylboronic Acid: Synthesis of 6-
Fluoroalkyl-Phenanthridines
Yinwei Bao, Zhuo Wang, Chen Chen*, Bolin Zhu*, Yuebo Wang, Jinghui Zhao, Jinyu Gong, Mengya Han
and Chang Liu
Leave this area blank for abstract info.
#
#
Tianjin Key Laboratory of Structure and Performance for Functional Molecules, MOE Key Laboratory of
Inorganic-Organic Hybrid Functional Material Chemistry, College of Chemistry, Tianjin Normal University,
Tianjin 300387, P. R. China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Palladium-Catalyzed Tandem Cyclization of Fluorinated Imidoyl Chlorides with 2-
Bromophenylboronic Acid: Synthesis of 6-Fluoroalkyl-Phenanthridines
#
#
Yinwei Bao, Zhuo Wang, Chen Chen*, Bolin Zhu*, Yuebo Wang, Jinghui Zhao, Jinyu Gong, Mengya
Han and Chang Liu
Tianjin Key Laboratory of Structure and Performance for Functional Molecules, MOE Key Laboratory of Inorganic-Organic Hybrid Functional Material
Chemistry, College of Chemistry, Tianjin Normal University, Tianjin 300387, P. R. China. Email: tjnuchenchen@163.com, hxxyzbl@gmail.com
#
Yinwei Bao and Zhuo Wang contributed equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient method has been developed to synthesize 6-fluoroalkyl-phenanthridines via the
palladium-catalyzed tandem cyclization of fluorinated imidoyl chlorides with 2-
bromophenylboronic acid. This methodology facilitates the rapid synthesis of 6-fluoroalkyl-
phenanthridines through dual C–C bond formation in an oxidant-free one-pot manner.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Fluorinated imidoyl chlorides
Tandem cyclization
6
-Fluoroalkyl-phenanthridines
1
. Introduction
Phenanthridines are ubiquitous fused-heterocyclic motifs found
[
1]
in many biologically active molecules, pharmaceuticals and
[2]
natural
products.
In
particular,
fluoroalkyl-containing
phenanthridines often increase metabolic stability and lipophilicity,
[
3]
which have the potential to improve their biological functions.
Hence, it is essential to explore efficient methodologies for the
synthesis of 6-fluoroalkyl-phenanthridines and consequently many
[
4-9]
powerful synthetic strategies have been developed in this area.
The retrosynthetic analysis of 6-fluoroalkyl-phenanthridines can be
oriented to C–C bond (I, III, and IV, Scheme 1a) and C–N bond
formations (II, Scheme 1a). Utilizing an one bond formation
[4]
strategy, Fu and co-workers developed intramolecular cyclization
of N-biaryltrifluoroacetimidoyl chloride to realize III bond formation
for the construction of 6-trifluoromethyl-phenanthridines (Scheme
1b), but the low bonding efficiency limits its application. Presently,
a strategy to synthesize 6-trifluoromethyl-phenanthridines via two
or more chemical bond formations in a single step is desired. For
[
5]
[6]
instance, Studer and others achieved trifluoromethylation of 2-
arylisocyanides by using radical trifluoromethylating reagents,
where III and IV bonds were formed (Scheme 1c). For the
[
7]
formation of I and III bonds, Zhang and co-workers developed a
tandem Suzuki/C–H arylation reaction of N-(2-bromophenyl)-
trifluoroacetimidoyl chlorides with arylboronic acids to prepare 6-
trifluoromethyl-phenanthridines (Scheme 1d). However, the
requirement of a stoichiometric oxidant limits its application and
Scheme 1. Retrosynthetic analysis for the construction of 6-fluoroalkyl-
phenanthridines

2
Tetrahedron
compared to the functionalization on
t
A
heCC
A
E
r
P
ing
T
,
E
t
D
he MAN[d] USCRIPT
10
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
DPPF
Cs
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
50%
25%
36%
53%
functionalization on the C ring is difficult due to the starting
materials not being readily available. Very recently, our group
developed palladium-catalyzed norbornene-mediated
dehydrogenative annulation approach to synthesize 6-fluoroalkyl-
phenanthridines from aryl iodides and fluorinated imidoyl chlorides
[
8]
[d]
11
DPPE
a
[
d]
1
1
1
1
2
3
4
5
DPPB
[e]
P(4-F-C
P(4-F-C
P(4-F-C
6
6
6
H
H
H
4
4
4
)
3
)
3
)
3
3
(
Scheme 1e). As a continuation of our interest in the synthesis of
[
[
[
f]
[c]
[8, 10]
ND
halogen-containing heterocycles,
we hope to develop new
approaches for the synthesis of 6-fluoroalkyl-phenanthridines via I
and III bond formation in a one-pot system. We envision that
biologically relevant 6-fluoroalkyl-phenanthridines can be obtained
from the combination of fluorinated imidoyl chlorides and 2-
bromophenylboronic acid through a palladium-catalyzed tandem
cyclization reaction and believe that functionalization on the C ring
g]
h]
33%
15%
61%
16
Pd(OAc)2
Pd(PPh
Pd (dba)
Pd(dppf)Cl
PdCl (PPh
P(4-F-C H )
6
4
2
Cs CO3
17
18
19
20
21
22
3
)
4
------
------
------
------
------
------
Cs
Cs
Cs
2
2
2
CO
CO
CO
3
3
3
[c]
2
3
ND
[7]
is easier compared to Zhang’s work. (Scheme 1f).
2
45%
97%
82%
79%
2
. Results/Discussion
2
3
)
2
2 3
Cs CO
Initially, the reaction of 2-bromophenylboronic acid 1a with
fluorinated imidoyl chloride 2a, was conducted under a nitrogen
[
i]
PdCl
PdCl
2
(PPh
3
)
2
Cs
Cs
2
CO
3
3
atmosphere with 10 mol% Pd(OAc)
2
as the catalyst and 20 mol%
CO (base) in toluene at
20 C. After 12 h, the desired product 3 was obtained in 51%
isolated yield (Table 1, entry 1). Screening of bases revealed
Cs CO to be the optimal base (Table 1, entries 2-5).
[j]
2
(PPh
3
)
2
2
CO
PPh as the ligand in the presence of Cs
3
2
3
o
1
[a]
Reaction Conditions: the reactions were carried out with 1a (0.48
mmol), 2a (0.4 mmol), [Pd] (0.04 mmol), ligand (0.08 mmol), base (0.8
[b]
2
3
mmol), toluene (3.0 mL) under a nitrogen atmosphere for 12 h. isolated
[
c]
[d]
[e]
[f]
Subsequently, a series of ligands including diphosphines and
monophosphines were evaluated for this transformation, and to
our delight, the yield of 3 was significantly increased to 81% with
yield. ND = not detected. ligand (10 mol %). MeCN 3.0 mL. DMF
[
g]
[h]
[i]
3.0 mL.
o-xylene 3.0 mL.
DCE 3.0 mL. 1a (0.4 mmol), 2a (0.6
[
j]
o
mmol). the reaction was run at 100 C.
6 4 3
the use of P(4-F-C H ) as the ligand (Table 1, entries 6-12). To
[
a]
further improve the yield, a range of solvents were tested,
including MeCN, DMF, o-xylene, and DCE, but toluene was found
to be most efficient (compare entry 8 with entries 13-16). Among
the Pd(0) and Pd(II) catalysts investigated, Pd(II) catalysts were
found to be the most efficient (Table 1, entries 17-20). It is worth
noting that 97% yield could be obtained via the catalysis with
Table 2. Substrate scope of the reaction .
PdCl2(PPh3)2 (10 mol%)
Cs2CO3 (2.0 equiv)
RF
B(OH)2
Br
RF
N
N
R1
+
R2
R1
R2
Cl
toluene, 120 oC, N2, 12 h
1
2
3-22
(1.2 equiv)
(1.0 equiv)
PdCl
2 3 2
(PPh ) (Table 1, entry 20). Further investigation regarding
the ratio of 1a and 2a did not give a better result (Table 1, entry
F3C
F3C
F3C
F3C
o
N
N
N
N
Me
2
1). In addition, lowering the reaction temperature to 100 C gave
an inferior result (Table 1, entry 22). Finally, the reaction of 1a (1.2
equiv) with 2a (1.0 equiv) in the presence of PdCl (PPh (10
mol%) and Cs CO (2.0 equiv) in toluene under nitrogen
atmosphere at 120 °C for 12 h was the optimal condi tion.
3
Me
1
2
3
)
2
4 (95%)
Me
5 (96%)(5:1)[b]
6 (86%)[c]
3
(97%)
2
3
F3C
F3C
F3C
F3C
N
N
N
N
OMe
[
a]
Table 1. Optimization of reaction conditions
.
OMe
C(Ph)3
Me
F
7
(88%)
8 (57%)
9 (90%)
10 (45%)
F3C
F3C
F3C
F3C
N
N
N
Cl
N
Cl
Me
11 (52%)
12 (43%)
1
3 (75%)
14 (74%)
F3C
[
b]
entry
[Pd]
ligand
base
Cs CO
Na CO
PO
yield(%)
51%
F3C
F3C
F3C
N
N
N
N
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
2
3
Me
MeO
MeO
Me
F3C
[
[
[
c]
c]
c]
MeO
15 (47%)[c]
F3C
16 (68%)[c]
2
3
ND
ND
ND
17 (72%)
[c]
18 (63%)[c]
K
3
4
ClF2C
C2F5
C2F5
N
N
N
N
Me
NaOH
KOAc
F3C
OMe
9 (39%)[c]
21 (69%)
22 (81%)
1
20 (55%)
25%
[
a]
Reaction conditions: the reactions were carried out with 1 (0.48 mmol),
[
c]
P(2-Me-C
P(4-Me-C
6
H
H
4
)
3
3
Cs
Cs
Cs
Cs
2
2
2
2
CO
CO
CO
CO
3
3
3
3
ND
ND
2
(0.4 mmol), PdCl
2
(PPh
3
)
2
(0.04 mmol), Cs
2
CO
3
[
(0.8 mmol) in toluene
b]
[
c]
(3.0 mL) under a nitrogen atmosphere for 12 h.
Regioselectivity ratio
6
4
)
(
the major isomer is substituted at the 3-position as indicated，major
[
c]
2 3
isomer: 80% yield, minor isomer: 16% yield). Cs CO (6.0 equiv)
P(4-F-C
P(4-CF
6
H
4
)
3
81%
62%
3
-C
6
H
4
)
3
With the optimized reaction conditions known, we next
surveyed the substrate scope of this reaction (Table 2).

3
First,
a
variety of fluorinated imidoyl chlo
A
rid
C
esCE
w
PTED MANUSCRIPT
er
e
investigated, which could be easily prepared from fluorinated
carboxylic acids and the corresponding aniline. p-, m-, o-
methyl substituents on the phenyl ring of 2 were well
tolerated, and the desired 6-fluoroalkyl-phenanthridines 4-6
were isolated in 86%-96% yields. Among them, 5 was
obtained with good regioselectivity (5:1) when m-methyl-
substituted substrate was used. Moreover, various
fluorinated imidoyl chlorides containing electron-donating (-
To gain more insight into the details of this transformation,
a series of control experiments were carried out. First, to
understand the C–H activation process, the kinetic isotope
effect (KIE) was measured by intermolecular competition
experiments under the standard conditions, and the KIE
value was found to be 1.5, which suggested the C–H bond
cleavage was not involved in the rate-determining step of
the catalytic cycle (Scheme 2a). When non-fluorinated
imidoyl chloride 23 was used instead of 2, the corresponding
annulation product 24 was not detected in the reaction, and
ca. 70% yield of 25 was isolated. It is likely that the strong
OMe, -C(Ph)
3
)
and electron-withdrawing (-F, -Cl)
substituents attached at the o- and p-position participated in
this reaction, producing the desired products in moderate to
good yields (7-12). Fluorinated imidoyl chloride with multiple
substituents was also employed, providing 13 in 75% yield.
Likewise, 6-(trifluoromethyl)benzo[c]phenanthridine, 14, was
also obtained (74% yield) in our reaction system.
electron-withdrawing ability of the CF
activate the C–Cl bond.
3
group is essential to
Furthermore, the cyclization
[
11]
product 27 was not detected with styrene derivative 26 as
the substrate, which signified that the imine group may
played a key role in promoting oxidative addition and the C–
H activation processes via the coordination with Pd species
(Scheme 2b). Intermolecular competition experiments
between electronically distinct substituted fluorinated imidoyl
chlorides were attempted and substrates with electron-
donating groups were preferentially converted (Scheme 2c).
To further validate the sequence of the formation of the two
new chemical bonds, two control experiments were
conducted. First, with the reaction between 1a and 2a under
Subsequently,
various
substituents
on
the
2-
bromophenylboronic acid were tested, along with multi-
substituted fluorinated imidoyl chlorides, and all of them
reacted efficiently, providing the corresponding products 15-
19 in 39%-72% yield. Notably, in addition to CF
3
, different
CF could
fluorine-containing groups, such as CF Cl, CF
also be introduced on phenanthridines through this
transformation (20-22). It should be noted that, in some
cases, 6.0 equiv of Cs
satisfactory results.
2
2
3
2 3
CO were required to achieve
o
standard conditions at 60 C for 6 h, 3 was not detected,
while 28 was isolated in 97% yield. Subsequently, 28 could
be converted into the corresponding 6-fluoroalkyl-
phenanthridine in 99% yield under standard conditions at
o
1
20 C, which demonstrated the preferential formation of III
bond.
On the basis of these results and previous reports,
[
7]
a
possible mechanism is proposed in Scheme 3. The reaction
may proceed through a Pd(0)/Pd(II) pathway although a
[12, 13]
Pd(II)/Pd(IV) pathway could not be dismissed.
First,
Pd(0) reacts with fluorinated imidoyl chloride 2a to produce
the Pd(II) intermediate A via oxidative addition. This is
followed by transmetallation with 1a to form the Pd(II)
intermediate B, and the following C–Pd(II)–C reductive
elimination affords 28 and regenerates the Pd(0) catalyst.
Subsequently, the oxidative addition of the C–Br bond,
followed by C–H activation can provide a seven-membered
metallacyclic Pd(II) intermediate D, which undergoes
reductive elimination to give the desired product 3 and
regenerates the Pd(0) catalyst species to complete the
catalytic cycle. Further study on the details of the
mechanism is in process.
Scheme 2. Control experiments
Scheme 3. Possible mechanism

4
Tetrahedron
1
White solid (100 mg, 96%). M.p.: 64-66 ºC. H NMR (400 MHz,
ACCEPTED MANUSCRIPT
CDCl ) δ 8.96 (d, J = 8.6 Hz, 0.2 H), 8.66 (d, J = 8.4 Hz, 1H),
3
8
8
.48 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 8.4 Hz, 0.22H), 8.36 (d, J =
.4 Hz, 1H), 8.19 (d, J = 7.9 Hz, 0.2H), 8.09 (s, 1H), 7.91 (m,
3
. Conclusion
In conclusion, we have developed a Pd-catalyzed tandem
1.18H), 7.81 – 7.67 (m, 1.41H), 7.66 – 7.57 (m, 1.16H), 3.13 (s,
13
0
3
1
1
1
2
.6H), 2.61 (s, 3H). C NMR (100 MHz, CDCl ) δ 146.50 (q, J =
cyclization of fluorinated imidoyl chlorides using 2-
bromophenylboronic acid for the synthesis 6-fluoroalkyl-
phenanthridines without the use of an oxidant. Fluorinated imidoyl
chlorides served as fluorine-containing synthons for the
construction of fluorinated heterocycles, which could be easily
prepared from simple starting materials. Therefore, this strategy
can be considered as a route for the synthesis of 6-fluoroalkyl-
phenanthridines.
3
2.8 Hz), 143.31, 141.96, 139.69, 135.23, 135.06, 134.06, 133.45,
31.24, 130.98, 130.61, 130.44, 130.10, 128.40, 127.56, 127.20,
26.94, 125.90 (q, J = 3.2 Hz), 125.81 (q, J = 3.6 Hz), 122.82,
22.68, 122.35, 121.99 (q, J = 277.1 Hz), 121.81, 121.52, 26.66,
19
1.40. F NMR (376 MHz, CDCl ) δ -63.33 (s), -63.44 (s). ESI-
3
+
MS: Calcd for C H F N: [M+H ] 262.0838, found 262.0840.
15
10 3
4.2.4 4-methyl-6-(trifluoromethyl)phenanthridine (6)
4
. Experimental Section
1
White solid (90 mg, 86%). M.p.: 53-55 ºC. H NMR (400 MHz,
CDCl ) δ 8.65 (d, J = 8.4 Hz, 1H), 8.43 – 8.34 (m, 2H), 7.91 –
3
4
.1. General information:
7
3
1
.84 (m, 1H), 7.77 – 7.71 (m, 1H), 7.66 – 7.61 (m, 2H), 2.90 (s,
1
3
1
13
19
H). C NMR (100 MHz, CDCl ) δ 144.82 (q, J = 32.9 Hz),
The H NMR, C NMR, and F NMR were recorded with
Bruker 400 MHz spectrometer instruments in CDCl . The
chemical shifts (δ) of H NMR and C NMR were measured in
ppm, referenced to residual H and C signals of nondeuterated
3
40.53, 139.44, 134.24, 130.91, 129.89, 128.74, 127.73, 125.71
q, J = 3.3 Hz), 124.98, 122.72, 122.10 (q, J = 277.0 Hz), 121.51,
19.70, 17.93. F NMR (376 MHz, CDCl ) δ -63.43 (s). ESI-MS:
3
+
3
1
13
(
19
1
13
1
Calcd for C H F N: [M+H ] 262.0838, found 262.0840.
CDCl (δ = 7.26 and 77.00), as internal standards. All solvents
15 10 3
3
were obtained from commercial sources and were purified
according to standard procedures. Purification of products was
accomplished by flash chromatography using silica gel (200~300
mesh). Thin layer chromatography (TLC) was performed on
Merck silica gel GF254 plates and visualized by UV-light (254
nm). Melting points were obtained on a Yanaco-241 apparatus
and are uncorrected. HRMS were recorded on VG ZAB-HS mass
spectrometer with ESI resource. Substituted imidoyl chlorides
4.2.5 2-methoxy-6-(trifluoromethyl)phenanthridine (7)
1
White solid (98 mg, 88%). M.p.: 103-105 ºC. H NMR (400 MHz,
CDCl ) δ 8.62 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.20
3
(d, J = 9.0 Hz, 1H), 7.93 – 7.85 (m, 2H), 7.81 – 7.69 (m, 1H),
13
7.43 (dd, J = 9.0, 2.7 Hz, 1H), 4.05 (s, 3H). C NMR (100 MHz,
CDCl ) δ 160.19, 143.96 (q, J = 32.8 Hz), 137.07, 133.33, 132.65,
3
[
8]
were synthesized according to the literature procedures. Other
substituted 2-bromophenylboronic acids were commercially
available.
130.80, 128.10, 126.57, 125.86 (q, J = 3.3 Hz), 122.54, 122.17 (q,
19
J = 276.7 Hz), 122.02, 119.38, 102.87, 55.74. F NMR (376
MHz, CDCl ) δ -63.18 (s). ESI-MS: Calcd for C H F NO:
3
15 10 3
+
[
M+H ] 278.0787, found 278.0786.
4
.2 General procedure for the synthesis of 3-22
4
.2.6 4-methoxy-6-(trifluoromethyl)phenanthridine (8)
A sealed tube contained PdCl (PPh ) (10 mol %, 0.04 mmol)
2
3 2
and Cs CO (0.8 ~ 2.4 mmol) was evacuated and purged with
1
2
3
White solid (63 mg, 57%). M.p.: 105-107 ºC. H NMR (400 MHz,
nitrogen gas three times. Then, 1 (0.48 mmol) and 2 (0.4 mmol)
in toluene (3.0 mL) were added to the system via syringe under a
nitrogen atmosphere and the reaction was allowed to stir at
CDCl ) δ 8.68 (d, J = 8.4 Hz, 1H), 8.44 – 8.36 (m, 1H), 8.18 (d, J
8.1 Hz, 1H), 7.95 – 7.88 (m, 1H), 7.81 – 7.69 (m, 2H), 7.21 (d,
J = 7.9 Hz, 1H), 4.14 (s, 3H). C NMR (100 MHz, CDCl ) δ
156.71, 145.06 (q, J = 33.3 Hz), 133.94, 132.92, 131.28, 129.75,
128.22, 126.59, 125.87 (q, J = 3.2 Hz), 123.09, 122.02 (q, J =
3
=
13
3
1
20 °C for 12 h. The reaction solution was concentrated in vacuo
and the residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate, 100:1) to afford the desired
pure products 3-22.
19
276.8 Hz), 121.97, 113.80, 109.02, 56.49. F NMR (376 MHz,
+
CDCl ) δ -63.02 (s). ESI-MS: Calcd for C H F NO: [M+H ]
3
15 10 3
2
78.0787, found 278.0786.
4
.2.1 6-(trifluoromethyl)phenanthridine (3)
4
.2.7 6-(trifluoromethyl)-2-tritylphenanthridine (9)
1
White solid (96 mg, 97%). M.p.: 63-65 ºC. H NMR (400 MHz,
CDCl ) δ 8.70 (d, J = 8.4 Hz, 1H), 8.63 – 8.59 (m, 1H), 8.42 –
.36 (m, 1H), 8.32 – 8.27 (m, 1H), 7.96 – 7.90 (m, 1H), 7.85 –
1
3
Yellow solid (176 mg, 90%). M.p.: 160-162 ºC. H NMR (400
MHz, CDCl ) δ 7.41 (dd, J = 7.9, 1.0 Hz, 1H), 7.18 (td, J = 7.4,
8
7
13
3
.75 (m, 3H). C NMR (100 MHz, CDCl ) δ 146.55 (q, J = 32.8
3
1
6
2
1
1
2
.2 Hz, 1H), 7.14 (dd, J = 7.8, 1.9 Hz, 1H), 7.12 – 7.05 (m, 10H),
Hz), 141.81, 134.00, 131.35, 131.18, 129.32, 129.20, 128.05,
.99 – 6.97 (m, 5H), 6.95 – 6.90 (m, 2H), 6.65 (d, J = 8.7 Hz,
1
2
25.95 (q, J = 3.0 Hz), 125.14, 122.54, 122.06, 121.95 (q, J =
13
H). C NMR (100 MHz, CDCl ) δ 155.86 (q, J = 35.3 Hz),
1
9
3
77.1 Hz), 121.81. F NMR (376 MHz, CDCl ) δ -63.45 (s).
ESI-MS: Calcd for C H F N: [M+H ] 248.0682, found 248.0680.
3
46.44, 145.01, 144.26, 133.01, 132.76, 131.33, 131.29, 131.07,
+
1
4
8 3
30.29, 127.41, 127.19, 126.00, 121.41, 120.08, 119.34 (q, J =
19
79.2 Hz), 64.58. F NMR (376 MHz, CDCl ) δ -70.11 (s). ESI-
3
+
4
.2.2 2-methyl-6-(trifluoromethyl)phenanthridine (4)
MS: Calcd for C H F N: [M+H ] 490.1777, found 490.1776.
33
22 3
1
White solid (99 mg, 95%). M.p.: 65-67 ºC. H NMR (400 MHz,
4.2.8 2-fluoro-6-(trifluoromethyl)phenanthridine (10)
CDCl ) δ 8.61 (d, J = 8.4 Hz, 1H), 8.39 – 8.28 (m, 2H), 8.14 (d, J
8.4 Hz, 1H), 7.90 – 7.80 (m, 1H), 7.72 (m, 1H), 7.60 (dd, J =
.4, 1.6 Hz, 1H), 2.63 (s, 3H). C NMR (100 MHz, CDCl ) δ
45.46 (q, J = 32.8 Hz), 140.00, 139.45, 133.54, 131.02, 131.00,
30.71, 127.80, 125.73 (q, J = 3.3 Hz), 124.88, 122.40, 122.02 (q,
J = 276.8 Hz), 121.76, 121.57, 22.07. F NMR (376 MHz,
CDCl ) δ -63.30 (s). ESI-MS: Calcd for C H F N: [M+H ]
3
=
1
White solid (48 mg, 45%). M.p.: 84-86 ºC. H NMR (400 MHz,
13
8
1
1
3
CDCl ) δ 8.57 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.29
3
(
dd, J = 9.0, 5.6 Hz, 1H), 8.20 (dd, J = 9.9, 2.7 Hz, 1H), 7.97 –
13
7
.91 (m, 1H), 7.84 – 7.78 (m, 1H), 7.55 (m, 1H). C NMR (100
19
MHz, CDCl ) δ 162.68 (d, J = 250.6 Hz), 145.90 (q, J = 33.3 Hz),
+
3
3
15 10 3
1
1
1
38.63, 133.60 (d, J = 9.5 Hz), 133.41 (d, J = 4.4 Hz), 131.42,
28.73, 126.79 (d, J = 9.5 Hz), 126.03 (q, J = 3.3 Hz), 122.72,
21.88 (q, J = 276.9 Hz), 121.85, 118.47 (d, J = 24.5 Hz), 107.18
2
62.0838, found 262.0840.
19
4
.2.3 3-methyl-6-(trifluoromethyl)phenanthridine (5)
(d, J = 23.7 Hz). F NMR (376 MHz, CDCl ) δ -63.49 (s), -
3

5
+
13
1
08.78 (s). ESI-MS: Calcd for C H F N: [M+H ] 266.0587,
2.5 Hz, 1H), 4.00 (s, 3H). C NMR (100 MHz, CDCl ) δ
3
14
7
4
ACCEPTED MANUSCRIPT
found 266.0586.
158.80, 143.53 (q, J = 32.9 Hz), 137.86, 132.73, 132.07, 130.11,
1
1
5
28.99, 127.59, 127.55, 124.65, 124.46, 123.85, 122.91, 122.84,
22.48 (q, J = 275.6 Hz), 119.13, 104.52 (q, J = 3.3 Hz),
4
.2.9 2-chloro-6-(trifluoromethyl)phenanthridine (11)
1
9
5.53. F NMR (376 MHz, CDCl ) δ -63.57 (s). ESI-MS: Calcd
3
+
1
for C H F NO: [M+H ] 328.0944, found 328.0945.
19 12 3
White solid (59 mg, 52%). M.p.: 76-78 ºC. H NMR (400 MHz,
CDCl ) δ 8.54 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.36
3
4
.2.15 8-methoxy-1,3-dimethyl-6-(trifluoromethyl)phenanthridine
(
d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.95 – 7.87 (m, 1H),
13
(17)
7
.82 – 7.75 (m, 1H), 7.72 (dd, J = 8.8, 2.2 Hz, 1H). C NMR
(100 MHz, CDCl ) δ 146.65 (q, J = 33.2 Hz), 140.05, 135.39,
3
1
1
3
32.83, 132.48, 131.60, 129.92, 128.69, 126.07, 125.95 (q, J =
.1 Hz), 122.47, 121.74 (q, J = 277.2 Hz), 121.85, 121.71.
White solid (88 mg, 72%). M.p.: 140-142 ºC. H NMR (400 MHz,
19
F
CDCl ) δ 8.85 (d, J = 9.5 Hz, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.51
3
NMR (376 MHz, CDCl ) δ -63.52 (s). ESI-MS: Calcd for
(dd, J = 9.4, 2.7 Hz, 1H), 7.44 (s, 1H), 4.01 (s, 3H), 3.06 (s, 3H),
3
+
13
C H ClF N: [M+H ] 282.0292, found 282.0294.
2.55 (s, 3H). C NMR (100 MHz, CDCl ) δ 157.67, 145.29 (q, J
=
14
7
3
3
32.8 Hz), 142.77, 137.48, 135.25, 133.85, 129.83, 129.59,
1
28.12, 123.92, 122.72, 122.16 (q, J = 277.3 Hz), 120.88, 105.99
4
.2.10 4-chloro-6-(trifluoromethyl)phenanthridine (12)
19
(
q, J = 3.6 Hz), 55.49, 26.52, 20.93. F NMR (376 MHz, CDCl )
3
+
1
δ -63.97 (s). ESI-MS: Calcd for C H F NO: [M+H ] 306.1100,
17 14 3
White solid (48 mg, 43%). M.p.: 125-127 ºC. H NMR (400 MHz,
CDCl ) δ 8.59 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.40
–
1
found 306.1101.
3
8.32 (m, 1H), 7.94 – 7.87 (m, 1H), 7.84 (dd, J = 7.6, 1.1 Hz,
13
4
.2.16 6,8-bis(trifluoromethyl)phenanthridine (18)
H), 7.81 – 7.74 (m, 1H), 7.63 (t, J = 8.0 Hz, 1H). C NMR (100
MHz, CDCl ) δ 146.72 (q, J = 33.5 Hz), 138.13, 135.63, 133.70,
3
1
1
1
31.67, 129.65, 128.99, 128.60, 126.68, 125.90 (q, J = 3.4 Hz),
White solid (80 mg, 63%). M.p.: 83-85 ºC. H NMR (400 MHz,
19
22.74, 121.71 (q, J = 277.3 Hz), 121.69, 120.77. F NMR (376
CDCl ) δ 8.86 (d, J = 8.8 Hz, 1H), 8.71 – 8.61 (m, 2H), 8.36 (dd,
3
MHz, CDCl ) δ -63.37 (s). ESI-MS: Calcd for C H ClF N:
J = 8.0, 1.5 Hz, 1H), 8.14 (dd, J = 8.8, 1.6 Hz, 1H), 7.96 – 7.84
3
14
7
3
+
13
[
M+H ] 282.0292, found 282.0294.
(m, 2H). C NMR (100 MHz, CDCl ) δ 146.45 (q, J = 33.5 Hz),
3
1
1
1
42.47, 136.10, 131.46, 130.60, 130.08 (q, J = 32.4 Hz), 129.92,
27.29 (q, J = 3.0 Hz), 124.23, 123.79, 123.66 (q, J = 272.6 Hz),
23.51 (q, J = 4.2 Hz), 122.47, 121.62 (q, J = 277.1 Hz), 121.15.
4
.2.11 1,3-dimethyl-6-(trifluoromethyl)phenanthridine (13)
19
1
F NMR (376 MHz, CDCl ) δ -62.54 (s), -63.29(s). ESI-MS:
3
White solid (83 mg, 75%). M.p.: 133-135 ºC. H NMR (400 MHz,
CDCl ) δ 8.90 (d, J = 8.7 Hz, 1H), 8.40 (d, J = 8.3 Hz, 1H), 7.98
+
Calcd for C H F N: [M+H ] 316.0555, found 316.0553.
15
7 6
3
(
s, 1H), 7.92 – 7.83 (m, 1H), 7.74 (dd, J = 11.4, 4.0 Hz, 1H), 7.45
13
4
.2.17 2-methoxy-6,8-bis(trifluoromethyl)phenanthridine (19):
(s, 1H), 3.07 (s, 3H), 2.55 (s, 3H). C NMR (100 MHz, CDCl ) δ
3
1
1
1
46.18 (q, J = 32.8 Hz), 143.51, 138.52, 135.28, 135.22, 134.69,
30.35, 129.66, 126.69, 126.62, 125.76 (q, J = 3.3 Hz), 122.48,
1
White solid (54 mg, 39%). M.p.: 102-105 ºC. H NMR (400 MHz,
19
22.39, 122.05 (q, J = 277.1 Hz), 26.47, 20.96. F NMR (376
CDCl ) δ 8.75 (d, J = 8.6 Hz, 1H), 8.63 (s, 1H), 8.26 (d, J = 9.0
3
+
MHz, CDCl ) δ -63.32 (s). ESI-MS: Calcd for C H F N: [M+H ]
Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.52 (d, J = 8.7
3
16 12 3
13
2
76.0995, found 276.0993.
Hz, 1H), 4.07 (s, 3H). C NMR (100 MHz, CDCl ) δ 160.70,
3
1
3
2
43.79 (q, J = 33.6 Hz), 137.72, 135.33, 132.97, 130.07 (q, J =
3.1 Hz), 126.68 (q, J = 3.0 Hz), 125.74, 123.79, 123.69 (q, J =
72.4 Hz), 123.42 (q, J = 4.0 Hz), 121.85 (q, J = 276.5 Hz),
4
.2.12 6-(trifluoromethyl)benzo[c]phenanthridine (14)
19
1
121.38, 120.57, 103.29, 55.84. F NMR (376 MHz, CDCl ) δ -
6
3
3
White solid (88 mg, 74%). M.p.: 150-152 ºC. H NMR (400 MHz,
CDCl ) δ 9.44 (d, J = 8.3 Hz, 1H), 8.78 (d, J = 8.5 Hz, 1H), 8.56
+
2.55 (s), -63.00 (s). ESI-MS: Calcd for C H F NO: [M+H ]
16 9 6
3
46.0661, found 346.0611.
(
d, J = 9.0 Hz, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 9.0 Hz,
13
1
H), 7.97 (m, 2H), 7.81 (m, 2H), 7.77 – 7.69 (m, 1H). C NMR
4
.2.18 6-(chlorodifluoromethyl)phenanthridine (20)
(100 MHz, CDCl ) δ 144.87 (q, J = 33.4 Hz), 138.98, 134.23,
3
1
33.29, 132.07, 131.06, 130.16, 127.98, 127.86, 127.65, 125.77
1
(
q, J = 3.1 Hz), 125.00, 122.95, 122.77, 122.46, 122.34 (q, J =
White solid (58 mg, 55%). M.p.: 64-66 ºC. H NMR (400 MHz,
19
2
76.8 Hz), 119.35. F NMR (376 MHz, CDCl ) δ -62.89 (s).
CDCl ) δ 8.71 (d, J = 8.4 Hz, 1H), 8.64 – 8.56 (m, 1H), 8.57 –
3
3
+
ESI-MS: Calcd for C H F N: [M+H ] 298.0838, found
8.49 (m, 1H), 8.33 – 8.24 (m, 1H), 7.98 – 7.87 (m, 1H), 7.85 –
18
10 3
13
2
98.0839.
7.73 (m, 3H). C NMR (100 MHz, CDCl ) δ 149.97 (t, J = 26.0
3
Hz), 141.57, 134.30, 131.19, 129.32, 129.12, 127.77, 126.44 (t, J
=
4.3 Hz), 125.07, 122.62 (t, J = 223.8 Hz), 122.02, 121.20,
4
.2.13 8-methoxy-6-(trifluoromethyl)phenanthridine (15)
19
1
16.04. F NMR (376 MHz, CDCl ) δ -51.33 (s). ESI-MS: Calcd
3
+
1
for C H ClF N: [M+H ] 264.0386, found 264.0388.
14 8 2
White solid (52 mg, 47%). M.p.: 70-72 ºC. H NMR (400 MHz,
CDCl ) δ 8.61 (d, J = 9.2 Hz, 1H), 8.55 – 8.49 (m, 1H), 8.29 –
3
4
.2.19 6-(perfluoroethyl)phenanthridine (21)
8
.22 (m, 1H), 7.80 – 7.71 (m, 2H), 7.68 (d, J = 1.8 Hz, 1H), 7.55
13
(
m, 1H), 4.01 (s, 3H). C NMR (100 MHz, CDCl ) δ 159.04,
3
1
1
45.57 (q, J = 32.4 Hz), 141.06, 131.11, 129.24, 128.53, 128.32,
25.31, 124.15, 123.21, 122.49, 122.06 (q, J = 277.0 Hz), 121.58,
White solid (82 mg, 69%). M.p.: 71-73 ºC. H NMR (400 MHz,
CDCl ) δ 8.58 (d, J = 8.3 Hz, 1H), 8.46 (dd, J = 10.5, 8.6 Hz, 2H),
1
3
19
1
6
05.61 (q, J = 3.6 Hz), 55.59. F NMR (376 MHz, CDCl ) δ -
8.25 – 8.19 (m, 1H), 7.83 (t, J = 7.4 Hz, 1H), 7.78 – 7.68 (m, 3H).
3
+
13
4.10 (s). ESI-MS: Calcd for C H F NO: [M+H ] 278.0787,
C NMR (100 MHz, CDCl ) δ 146.49 (t, J = 26.4 Hz), 141.55,
15
10
3
3
found 278.0788.
133.80, 131.05, 129.21, 129.11, 127.83, 127.13, 125.86 (t, J =
6
3
.2 Hz), 124.64, 123.20, 122.48, 121.84, 119.31 (qt, J = 286.6,
19
5.4 Hz), 113.75 (tq, J = 256.3, 36.0 Hz). F NMR (376 MHz,
4
.2.14 8-methoxy-6-(trifluoromethyl)benzo[c]phenanthridine (16)
CDCl ) δ -80.13 (s), -106.76 (s). ESI-MS: Calcd for C H F N:
3
15
8 5
+
1
[M+H ] 298.0650, found 298.0649.
White solid(89 mg, 68%). M.p.: 155-157 ºC. H NMR (400 MHz,
CDCl ) δ 9.36 (d, J = 8.3 Hz, 1H), 8.56 (d, J = 9.2 Hz, 1H), 8.37
3
4
.2.20 4-methyl-6-(perfluoroethyl)phenanthridine (22)
(
d, J = 9.1 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 7.9 Hz,
1
H), 7.81 – 7.74 (m, 1H), 7.71 – 7.65 (m, 2H), 7.51 (dd, J = 9.2,

6
Tetrahedron
ACCEPTED MANUSCRIPT
Acknowledgments
1
White solid (101 mg, 81%). M.p.: 95-97 ºC. H NMR (400
MHz, CDCl ) δ 8.60 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 8.4 Hz, 1H),
3
8
.33 (dd, J = 6.7, 2.9 Hz, 1H), 7.87 – 7.81 (m, 1H), 7.71 (m, 1H),
13
We gratefully acknowledge the financial support from the
Science&Technology Development Fund of Tianjin Education
Commission for Higher Education (2018KJ159).
7
.63 – 7.57 (m, 2H), 2.82 (s, 3H). C NMR (100 MHz, CDCl ) δ
3
1
45.01 (t, J = 27.5 Hz), 140.17, 139.49, 134.17, 130.85, 129.77,
28.95, 127.66, 125.67 (t, J = 5.6 Hz), 124.60, 122.79, 122.05,
19.59, 119.42 (qt, J = 286.3, 34.9 Hz), 114.06 (tq, J = 255.8,
1
1
1
9
3
5.2 Hz), 17.80. F NMR (376 MHz, CDCl ) δ -79.66 (s), -
References and notes
3
+
1
05.65 (s). ESI-MS: Calcd for C H F N: [M+H ] 312.0806,
16
10 5
found 312.0808.
[
1] (a) Bernardo, P. H.; Wan, K.-F.; Sivaraman, T. ; Xu, J.; Moore, F. K.; Hung, A. W.;
Mok, H. Y. K.; Yu, V. C.; Chai, C. L. L. J. Med. Chem. 2008, 51, 6699. (b)
Merz, K.-H.; Muller, T.; Vanderheiden, S.; Eisenbrand, G.; Marko, D.; Bräse, S.
Synlett 2006, 20, 3461. (c) Zhu, S.; Ruchelman, A. L.; Zhou, N.; Liu, A. A.; Liu,
L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2005, 13, 6782. (d) Lewis, W. G.;
Green, L. G.; Grynszpan, F.; Radić, Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.;
Sharpless, K. B. Angew. Chem. 2002, 114, 1095. Angew. Chem., Int. Ed. 2002,
4
.2.21
trifluoroethylidene)aniline (28)
A sealed tube contained PdCl (PPh ) (10 mol %, 0.04 mmol)
(Z)-N-(1-(2-bromophenyl)-2,2,2-
2
3 2
and Cs CO (0.8 mmol) was evacuated and purged with nitrogen
2
3
gas three times. Then, 1a (0.48 mmol) and 2a (0.4 mmol) in
toluene (3.0 mL) were added to the system via syringe under a
nitrogen atmosphere and the reaction was allowed to stir at 60 °C
for 6 h. The reaction solution was concentrated in vacuo and the
residue was purified by column chromatography on silica gel
41, 1053. (e) Lynch, M. A.; Duval, O.; Sukhanova, A.; Devy, J.; MacKay, S. P.;
Waigh, R. D.; Nabiev, I. Bioorg. Med. Chem. Lett. 2001, 11, 2643.
[2] (a) Viladomat, F.; SeIIés, M.; Cordina, C.; Bastida, J. Planta Med. 1997, 63, 583.
(b) Ali, A. A.; El Saved, H. M.; Abdalliah, O. M.; Steglich, W. Phytochemistry
(petroleum ether/ethyl acetate, 100:1) to afford the desired pure
1986, 25, 2399. (c) Krane, B. D.; Fagbule, M. O.; Shamma , M.; Gözler, B. J.
product 28.
Nat. Prod. 1984, 47, 1.
[3]
(a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b) Purser, S.;
Moore, P. R.; Swallow, S.; Gouvermeur, V. Chem. Soc. Rev. 2008, 37, 320. (c)
Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (d) Zhu, J.; Xie, H.; Chen, Z.; Li,
S.; Wu, Y. Chem. Commun. 2011, 47, 1512. (e) Feng, Z.; Min, Q.-Q.; Xiao, Y.-
L.; Zhang, B.; Zhang, X. Angew. Chem., 2014, 126, 1695. Angew. Chem., Int. Ed.
1
2
7
4
8 Yellow oil (127 mg, 97%). H NMR (400 MHz, CDCl ) δ
3
.40 (d, J = 8.0 Hz, 1H), 7.24 – 7.17 (m, 1H), 7.16 – 7.06 (m,
13
H), 6.96 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 7.6 Hz, 2H). C NMR
(
100 MHz, CDCl ) δ 156.05 (q, J = 35.4 Hz), 146.48, 133.04,
3
1
1
32.49, 131.36, 130.34, 128.53, 127.17, 125.99, 121.24, 120.45,
19
2
014, 53, 1669. (f) Feng, Z.; Xiao, Y.-L., Zhang, X. Acc. Chem. Res. 2018, 51,
19.31 (q, J = 279.0 Hz). F NMR (376 MHz, CDCl3) δ -70.44
2
264.
+
(
s). ESI-MS: Calcd for C H BrF N: [M+H ] 327.9943, found
14 9 3
[4]
(a) Fu, W.; Zhu, M.; Xu, F.; Fu, Y.; Xu, C.; Zou, D. RSC Adv. 2014, 4, 17226. (b)
Zhu, M.; Fu, W.; Zou, G.; Xu, C.; Wang, Z. J. Fluorine Chem. 2014, 163, 23.
(a) Lübbesmeyer, M.; Leifert, D.; Schäfer, H.; Studer, A. Chem. Commun. 2018,
3
27.9941.
[5]
4
.3 KIE by intermolecular competition experiments:
5
4, 2240. (b) Gorbanev, Y.; Leifert, D.; Studer, A.; O’Connell, D.; Chechik, V.
A sealed tube contained PdCl (PPh ) (28.1 mg, 0.04 mmol,
2
3 2
Chem. Commun. 2017, 53, 3685. (c) Zhang, B.; Mück-Lichtenfeld, C.; Daniliuc,
C. G.; Studer, A. Angew. Chem., 2013, 125, 10992. Angew. Chem., Int. Ed. 2013,
1
0 mol %), and Cs CO (260.7 mg, 0.8 mmol, 2.0 equiv) was
2 3
evacuated and purged with nitrogen gas three times. Then, 1a
52, 10792. (d) Zhang, B.; Studer, A. Org. Lett. 2014, 16, 3990.
(96.4 mg, 0.48 mmol, 1.2 equiv), 2a (41.4 mg, 0.2 mmol, 0.5
[6]
(a) Wang, R.; Jiang, H.; Cheng, Y.; Kadi, A. A.; Fun, H.-K.; Zhang, Y.; Yu, S.
equiv) and 2a-D (42.5 mg, 0.2 mmol, 0.5 equiv) in toluene (3.0
mL) were added to the system via syringe under a nitrogen
atmosphere and the reaction mixture was stirred at 120 °C for 3 h.
The reaction solution was concentrated in vacuo and the residue
was purified by a short column chromatography on silica gel
Synthesis 2014, 46, 2711. (b) Cheng, Y.; Jiang, H.; Zhang, Y.; Yu, S. Org. Lett.
2013, 15, 5520. (c) Li, J.; Caiuby, C. A. D.; Paixão, M. W.; Li, C.-J. Eur. J. Org.
Chem. 2018, 2018, 2498. (d) Fang, J.; Shen, W.-G.; Ao, G.-Z.; Liu, F. Org. Chem.
Front. 2017, 4, 2049. (e) Sakamoto, R.; Kashiwagi, H.; Selvakumar, S.; Moteki,
S. A.; Maruoka, K. Org. Biomol. Chem. 2016, 14, 6417. (f) Liu, Y.-R.; Tu, H.-Y.;
Zhang, X.-G. Synthesis 2015, 47, 3460. (g) Wang, Y.; Wang, J.; Li, G.-X.; He, G.;
Chen, G. Org. Lett. 2017, 19, 1442. (h) Tang, X.; Song, S.; Liu, C.; Zhu, R.;
Zhang, B. RSC Adv. 2015, 5, 76363. (i) Stephens, D. E.; Chavez, G.; Valdes, M.;
Dovalina, M.; Arman, H. D.; Larionov, O. V. Org. Biomol. Chem. 2014, 12,
6190. (j) Wang, Q.; Dong, X.; Xiao, T.; Zhou, L. Org. Lett. 2013, 15, 4846. (k)
Lu, S.; Gong, Y.; Zhou, D. J. Org. Chem. 2015, 80, 9336. (l) Sun, X.; Yu, S. Org.
Lett. 2014, 16, 2938. (m) Gu, J.-W.; Zhang, X. Org. Lett. 2015, 17, 5384.
(
eluent EA) to afford a mixture. The solvent was then removed
1
under reduced pressure and H NMR showed K /K = 1.5.
H
D
4
.4 Intermolecular competition experiment:
A sealed tube contained PdCl (PPh ) (10 mol %, 0.04 mmol)
2
3 2
and Cs CO (0.8 mmol) was evacuated and purged with nitrogen
2
3
gas three times. Then, 1a (0.48 mmol), (Z)-2,2,2-trifluoro-N-(4-
methoxyphenyl)acetimidoyl chloride (0.4 mmol) and (Z)-2,2,2-
trifluoro-N-(4-fluorophenyl)acetimidoyl chloride (0.4 mmol) in
toluene (3.0 mL) were added to the system via syringe under a
nitrogen atmosphere and the reaction was allowed to stir at
[
7]
8]
9]
Wang, W.-Y.; Feng, X.; Hu, B.-L.; Deng, C.-L.; Zhang, X.-G. J. Org. Chem.
2013, 78, 6025.
[
[
Wang, Z.; Li, T.; Zhao, J.; Shi, X.; Jiao, D.; Zheng, H.; Chen, C.; Zhu, B.; Org.
Lett. 2018, 20, 6640.
1
20 °C for 12 h. The reaction solution was concentrated in vacuo
(a) Rong, J.; Deng, L.; Tan, P.; Ni, C.; Gu, Y.; Hu, J. Angew. Chem. 2016, 128
and the residue was purified by a short column chromatography
2
793. Angew. Chem., Int. Ed. 2016, 55, 2743. (b) Li, Y.; Zhu, J.; Zhang, L.; Wu,
on silica gel (eluent EA) to afford a mixture. The solvent was
Y.; Gong, Y. Chem. - Eur. J. 2013, 19, 8294. (c) Xu, C.; Song, X.; Guo, J.; Chen,
S.; Gao, J.; Jiang, J.; Gao, F.; Li, Y.; Wang, M. Org. Lett. 2018, 20, 3933. (d) Ge,
J.; Wang, X.; Liu, T.; Shi, Z.; Xiao, Q.; Yin, D. RSC Adv. 2016, 6, 19571.
1
then removed under reduced pressure and H NMR showed 7:10
=
1:0.3.
[
10] a) Han, F.; Yang, W.; Zhao, A.; Zheng, R.; Ji, C.; Liu, X.; Liu, G.; Chen, C. Asian
J. Org. Chem. 2018, 7, 1124. (b) Chen, C.; Hou, L.; Cheng, M.; Su, J.; Tong, X.
Angew. Chem. 2015, 127, 3135. Angew. Chem., Int. Ed. 2015, 54, 3092. (c) Chen,
C.; Hu, J.; Su, J.; Tong, X. Tetrahedron Lett. 2014, 55, 3229. (d) Chen, C.; Su, J.;
Tong, X. Chem. - Eur. J. 2013, 19, 5014. (e) Chen, C.; Tong, X. Org. Chem.
Front. 2014, 1, 439. (e) Liu, Q.; Chen, C.; Tong, X. Tetrahedron Lett. 2015, 56,
4
.5 Sequence of formation of the two new bonds:
A sealed tube contained PdCl (PPh ) (10 mol %, 0.04 mmol)
2
3 2
and Cs CO (0.8 mmol) was evacuated and purged with nitrogen
2
3
gas three times. Then, 28 (0.4 mmol) in toluene (3.0 mL) was
added to the system via syringe under a nitrogen atmosphere and
the reaction was allowed to stir at 120 °C for 12 h. The reaction
solution was concentrated in vacuo and the residue was purified
by column chromatography on silica gel (petroleum ether/ethyl
4
483.
[
11] Li, C.-L.; Chen, M.-W.; Zhang, X.-G. J. Fluorine Chem. 2010, 131, 856.
12] Chen, S.; Liu, Z.-S.; Yang, T.; Hua, Y.; Zhou, Z.; Cheng, H.-G.; Zhou, Q. Angew.
Chem., 2018, 130, 7279. Angew. Chem., Int. Ed. 2018, 57, 7161.
[
acetate, 100:1) to afford the desired pure product in 99% yield. 3
1
(
white solid, 98.0 mg). H NMR (400 MHz, CDCl ) δ 8.69 (d, J
3
[13] (a) Racowaki, J. M.; Ball, N. D.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133,
8022. (b) Topczewski, J. J.; Sanford, M. S. Chem. Sci. 2015, 6, 70.
=
8.4 Hz, 1H), 8.60 (dd, J = 6.8, 2.7 Hz, 1H), 8.42 – 8.35 (m, 1H),
1
8
.32 – 8.27 (m, 1H), 7.96 – 7.89 (m, 1H), 7.85 – 7.73 (m, 3H).