Palladium-catalyzed intramolecular C-H bond functionalization of trifluoroacetimidoyl chloride derivatives: Synthesis of 6-trifluoromethyl- phenanthridines

Article abstract of DOI:10.1016/j.jfluchem.2014.04.005

Highly efficient approaches to obtain 6-trifluoromethyl-phenanthridine derivatives have been realized through the palladium-catalyzed intramolecular C-H bond functionalization of trifluoroacetimidoyl chlorides. The reaction allows the direct formation of

Full text of DOI:10.1016/j.jfluchem.2014.04.005

Accepted Manuscript
Title: Palladium-catalyzed intramolecular C−H bond
functionalization of trifluoroacetimidoyl chloride derivatives:
Synthesis of 6-trifluoromethyl-phenanthridines
Author: Mei Zhu Weijun Fu Guanglong Zou Chen Xu
Zhiqiang Wang
PII:
S0022-1139(14)00096-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2014.04.005
FLUOR 8301
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
6-3-2014
8-4-2014
9-4-2014
Please cite this article as: M. Zhu, W. Fu, G. Zou, C. Xu, Z. Wang, Palladium-catalyzed
intramolecular CminusH bond functionalization of trifluoroacetimidoyl chloride
derivatives: Synthesis of 6-trifluoromethyl-phenanthridines, Journal of Fluorine
Chemistry (2014), http://dx.doi.org/10.1016/j.jfluchem.2014.04.005
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Palladium-catalyzed intramolecular C−H bond functionalization
of trifluoroacetimidoyl chloride derivatives: Synthesis of
6-trifluoromethyl-phenanthridines
a
a
b
a
a
Mei Zhu , Weijun Fu *, Guanglong Zou , Chen Xu , Zhiqiang Wang
a. College of Chemistry and Chemical Engineering, Luoyang Normal University,
Luoyang 471022, P. R. China
b. School of Chemistry and Enviromental Science, Guizhou Minzu Univeristy,
Guiyang 550025, P. R. China
E-Mail: wjfu@lynu.edu.cn
Highlights
►
Palladium-catalyzed intramolecular cyclization of trifluoroacetimidoyl
chlorides.
►
►
C -C bonds formation via C-H bond functionalization
Sp2
Sp2
The reaction afforded 6-trifluoromethyl-phenanthridines with good
functional group tolerance.
1
Page 1 of 22

Abstract: Highly efficient approaches to obtain 6-trifluoromethyl-phenanthridine
derivatives have been realized through the palladium-catalyzed intramolecular C−H
bond functionalization of trifluoroacetimidoyl chlorides. The reaction allows the
direct formation of CSp2-CSp2 bonds via C-H bond functionalization and rapid access
to phenanthridine ring systems in moderate to high yields with good functional group
tolerance.
Keywords: Palladium-catalyzed, Phenanthridines, Trifluoroacetimidoyl chlorides,
C-H functionalization
2
Page 2 of 22

1
. Introduction
Phenanthridine is a ubiquitous framework found in many natural products,[1-4]
biologically active molecules,[5-7] and optoelectronic materials.[8-10] Therefore,
molecules containing this motif have attracted considerable attention in medicinal
chemistry, and much effort has been focused on the synthetic methods of the
3
phenanthridine ring system.[11-17] In particular, CF -containing phenanthridines are
of significant interest because trifluoromethyl group enhance biological and
therapeutic activities of organic compounds. In 2013, Wu and co-workers reported
rhodium-catalyzed [2+2+2] cycloaddition reaction between diynes and alkynes
3
leading to CF -containing phenanthridines.[18] Zhang and co-workers described the
first example of a Pd-catalyzed tandem Suzuki/C-H arylation reaction of
N-aryltrifluoroacetimidoyl chlorides with arylboronic acids.[19] More recently,
Another efficient strategy to build the phenanthridine scaffold was based on
intermolecular radical addition/cyclization of 2-isocyanobiaryls with CF
developed by the groups of Studer, Zhou and Yu, respectively. [20-22]
Trifluoroacetimidoyl chlorides, easily prepared from commercially available
trifluoroacetic acid (TFA), amines, PPh , and Et N in CCl in a one-pot manner,[23]
3
radicals
3
3
4
are one kind of the most important intermediates and versatile building blocks in
organic synthesis.[24-26] For example, they are widely used as one of the coupling
3
Page 3 of 22

partners in transition-metal-catalyzed carbon-carbon bond formations via
cross-coupling reactions.[27-31] Meanwhile, transition-metal-catalyzed C(sp2)-Cl
bonds of trifluoroacetimidoyl chlorides were inserted into multiple bond have been
explored.[32] Recently, transition-metal-catalyzed C−H bond functionalization has
emerged as a useful, step-economical method for the direct conversion of C−H bonds
to C−C and C−heteroatom bonds.[33-38] Inspired by recent advance on
transition-metal-catalyzed direct C-H bond functionalizations and in parallel with our
continuing efforts to develop synthetic methods of CF
heterocycles,[39-42] we report here an efficient protocol for the synthesis of
-trifluoromethyl-phenanthridines via palladium-catalyzed intramolecular aromatic
3
-containing
6
C−H bond functionalization of trifluoroacetimidoyl chlorides (Scheme 1).
Scheme 1
2
. Results and discussion
Initially, we started to evaluate the reaction parameters by employing
N-biaryltrifluoroacetimidoyl chloride (1a) as model substrate. To our delight, the use
of 10 mol% Pd(OAc) as the catalyst, K CO (2.0 equiv) as the base and PPh as the
ligand in toluene could give the corresponding
-trifluoromethyl-phenanthridine 2a in 48% yield (Table 1, entry 1). Then we tried
other palladium source, such as Pd(PPh , Pd(PPh Cl and Pd(CH CN) Cl . The
results indicated that Pd(0) was more effective than Pd(II) species and Pd(PPh
displayed the highest reactivity in the model reaction (Table 1, entries 1-4). Then, we
investigated the effect of ligands [PPh , PCy , and P(tBu) ] on the reaction and
observed that the addition of PCy or P(tBu) as ligand afforded better yields of 72%
and 64%, respectively (Table 1, entries 5-6). The base also plays an important role in
the cyclization reaction. K CO was found to be the best one among the bases
investigated. Other bases such as K PO , Cs CO , and Na CO were inferior and
2
2
3
3
o
at
120 C
6
3
)
4
3
)
2
2
3
2
2
3 4
)
3
3
3
3
3
2
3
3
4
2
3
2
3
generated 2a in 37-54% yields (Table 1, entries 7-9). Only a trace amount of 2a was
4
Page 4 of 22

detected when KOAc was used as a base (Table 1, entry 10). Polar solvents such as
DMF, DMSO and CH CN were unfavorable for this transformation (Table 1, entries
1-13).
3
1
Table 1
With the optimized conditions in hand, we then explored the scope and
generality of the present process, and the results are summarized in Table 2. As
shown in Table 2, a variety of substituents (such as Me, OMe, F, Cl, and CF
3
) on the
4'-position of the aromatic ring were applicable, affording the cyclized products in
good yields (Table 2, entries 1-7). The reaction also worked well with 2'-substituted
substrate, albeit giving the products in moderate yields (Table 2, entries 8-9). As
expected, 3'-substituted substrate 1k gave a mixture of two regioselective products
(products 2k/2k'). In addition, 2-thiophenyl trifluoroacetimidoyl chloride 1l were also
viable substrate to provide a thieno-[3,2-c]quinoline system (2l). Subsequently, the
effect of the substituents on the aromatic ring attached to trifluoroacetimidoyl chloride
was screened. In all cases, substrates 1m–q proceeded smoothly to give the
corresponding products 2m–q in moderate to good yields (Table 2, entries 12-16).
Likewise, the perfluoroalkylated substrate 1r was also tested in this cyclization
reaction, and the corresponding 6-perfluoroalkylated phenanthridine 2r was formed
smoothly. The structure of 2r was unequivocally confirmed by single-crystal X-ray
analysis (Figure 1).[43]
Table 2
Figure 1
To gain insight into the mechanism, we tried the TEMPO-trapping experiment.
That is, treatment of 1a in the presence of TEMPO (1.2 equiv), Pd(PPh
3 4
) (10 mol %),
PCy (20 mol %), K CO (2.0 equiv) in toluene at 120 °C for 12 h afforded the
3
2
3
cyclized product 2a in 70% yield (Scheme 2). This result indicated that radical
5
Page 5 of 22

pathway can be ruled out.
Scheme 2
A proposed reaction mechanism was shown in Scheme 3. the oxidative addition
of trifluoroacetimidoyl chloride 1 to Pd(0) species afforded intermediate A.
Subsequently, A underwent an intramolecular electrophilic aromatic palladation
through C-H activation of the aromatic hydrogen, and subsequent proton
abstraction,[44-45] forming the palladacycle B, which followed by a reductive
elimination to afford the desired product 2.
Scheme 3
3
. Conclusion
In conclusion, we have developed an efficient method for the synthesis of
6-trifluoromethyl-phenanthridines through palladium-catalyzed intramolecular C−H
bond functionalization of trifluoroacetimidoyl chlorides. The result presented here
should be of considerable interest for valuable synthetic building blocks for medicinal
science.
4
. Experimental
4.1. General
Solvents were purified or dried in a standard manner. Reactions were monitored
by TLC on silica gel plates (GF254), and the analytical thin-layer chromatography
1
(
TLC) was performed on precoated, glass-backed silica gel plates. H NMR spectra
13
3
and C NMR spectra were measured in CDCl and recorded on on a 400 or 500 MHz
NMR spectrometers with TMS as an internal standard. Column chromatography over
silica gel (300–400 mesh) and petroleum ether/ethyl acetate combination was used as
6
Page 6 of 22

the eluent.
.2. Typical procedure for synthesis of 6-trifluoromethyl-phenanthridines
A mixture of N-biaryltrifluoroacetimidoyl chloride 1 (0.4 mmol), Pd(PPh
0 mol %), PCy (0.08 mol, 20 mol %), K CO (0.8 mol, 2 equiv) in toluene (4 mL)
was evacuated and backfilled with nitrogen (3 cycles) and then stirred at 120 °C for
2 h. After the reaction was completed, it was cooled to room temperature and diluted
4
3 4
) (0.04 mol,
1
3
2
3
1
with ethyl acetate. The resulting solution was directly filtered through a pad of silica
gel using a sintered glass funnel, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate = 10:1) to give the desired 6-trifluoromethyl-phenanthridines 2.
[
21]
4.2.1. 6-(trifluoromethyl)-8-methylphenanthridine (2a)
1
White solid, mp 107-109°C; H NMR (400 MHz, CDCl
3
): δ 8.36-8.48 (m, 2H), 8.20
(d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.64-7.72 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 2.53 (s,
13
3
H); C NMR (100 MHz, CDCl
3
): δ 146.0 (q, J = 32.6 Hz), 141.3, 138.2, 133.1,
131.7, 130.9, 129.1, 128.8, 125.1, 125.0, 122.2, 122.0 (q, J =275.2 Hz), 121.8, 21.9.
19
3
F NMR (376 MHz, CDCl ) δ -64.3 (s, 3 F).
[21]
4.2.2. 6-(trifluoromethyl)phenanthridine (2b)
1
White solid, mp 62-64°C; H NMR (500 MHz, CDCl
3
): δ 8.59 (d, J = 8.5 Hz, 1H),
8
7
1
1
4
.49-8.50 (m, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.19-8.20 (m, 1H), 7.81-7.84 (m, 1H),
13
.66-7.73 (m, 3H); C NMR (125 MHz, CDCl
3
): δ 146.5(q, J = 33.0 Hz), 141.8,
34.0, 131.4, 131.1, 129.3, 129.2, 128.1, 125.9 (q, J = 4.1 Hz), 125.1, 122.5, 122.1,
19
3
21.9 (q, J =275.6 Hz), 121.8. F NMR (376 MHz, CDCl ) δ -63.5 (s, 3 F).
.2.3. 8-ethyl-6-(trifluoromethyl)phenanthridine (2c)
1
White solid, mp 102-103°C; H NMR (400 MHz, CDCl
3
): δ 8.49-8.54 (m, 2H),
8.22-8.25 (m, 1H), 8.12 (s, 1H), 7.70-7.76 (m, 3H), 2.90 (q, J = 8.0 Hz, 2H), 1.36 (t, J
13
=
3
8.0 Hz, 3H); C NMR (100 MHz, CDCl ): δ 146.3 (q, J = 32.3 Hz), 144.4, 141.4,
1
1
2
32.1, 131.0, 129.1, 128.9, 125.2, 124.0 (q, J =3.5 Hz), 122.5, 122.1 (q, J =275.2 Hz),
19
22.0, 121.9, 29.2, 15.5. F NMR (376 MHz, CDCl ) ! -63.4 (s, 3 F); EI-MS (m/z):
B
B
+
76 [M
P
7
Page 7 of 22

[
21]
4.2.4. 6-(trifluoromethyl)-8-methoxyphenanthridine (2d)
1
White solid, mp 98-101°C; H NMR (400 MHz, CDCl
3
): δ = 8.44 (d, J = 9.2 Hz, 1H),
8
1
1
1
4
.37-8.39 (m, 1H), 8.19-8.21 (m, 1H), 7.66-7.70 (m, 2H), 7.59 (s, 1H), 7.42-7.45 (m,
13
H), 3.94 (s, 3H); C NMR (100 MHz, CDCl
3
): δ = 158.9, 145.4(q, J = 33.1 Hz),
40.9, 131.0, 129.2, 128.3, 128.26, 125.2, 124.0, 123.0, 122.4, 122.1 (q, J =275.1 Hz),
19
3
21.5, 105.4(q, J = 3.6 Hz), 55.5. F NMR (376 MHz, CDCl ) δ -64.1 (s, 3 F).
.2.5. 8-fluoro-6-(trifluoromethyl)phenanthridine (2e)
1
White solid, mp 87-89°C; H NMR (400 MHz, CDCl
3
): δ = 8.56-8.60 (m, 1H),
8
7
.42-8.44 (m, 1H), 8.21-8.23 (m, 1H), 7.93-7.95 (m, 1H), 7.72-7.77 (m, 2H),
13
3
.58-7.63 (m, 1H); C NMR (100 MHz, CDCl ): δ = 161.4 (d, J = 248.9 Hz), 145.6(q,
J = 29.4 Hz), 141.3, 131.2, 130.6(d, J = 1.9 Hz), 129.6, 129.2, 125.1(d, J = 9.0 Hz),
124.6, 122.7(d, J = 8.8 Hz), 121.8, 121.7(q, J = 275.1 Hz), 120.8 (d, J = 23.8 Hz),
19
1
3
10.7 (dq, J = 23.2 Hz, J = 3.4 Hz). F NMR (376 MHz, CDCl ) δ -63.99 (s, 3 F),
-109.92 (s, 1 F).
[
21]
4.2.6. 8-chloro-6-(trifluoromethyl)phenanthridine (2f)
1
White solid, mp 114-116°C; H NMR (400 MHz, CDCl
3
): δ = 8.48 (d, J = 8.8 Hz,
13
1
H), 8.41-8.43 (m, 1H), 8.25-8.27 (m, 1H), 8.19-8.22 (m, 1H), 7.71-7.79 (m, 3H); C
3
NMR (100 MHz, CDCl ): δ = 145.6(q, J = 33.1 Hz), 141.6, 134.2, 132.2, 132.0, 131.2,
129.67, 129.66, 125.1 (q, J =3.0 Hz), 124.4, 124.1, 122.4, 121.9, 121.6 (q, J = 274.6
19
Hz). F NMR (376 MHz, CDCl
3
) δ -63.6 (s, 3 F).
[
21]
4.2.7. 6,8-bis(trifluoromethyl)phenanthridine (2g)
1
3
White solid, mp 106-108°C; H NMR (500 MHz, CDCl ): δ = 8.80 (t, J = 8.5 Hz, 1H),
13
8
.60-8.63 (m, 2H), 8.31-8.32 (m, 1H), 8.10-8.11 (m, 1H), 7.83-7.90 (m, 2H); C
3
NMR (125 MHz, CDCl ): δ = 146.3 (q, J = 33.5 Hz), 142.4, 136.0, 131.4, 130.6,
1
1
30.1, 129.9, 129.8 (q, J = 4.1 Hz), 127.3, 124.2, 123.8, 123.6 (q, J = 270.9 Hz),
19
3
22.4, 121.6 (q, J = 275.3 Hz), 121.0. F NMR (376 MHz, CDCl ) δ -62.6 (s, 3 F),
-63.3 (s, 3 F).
[
21]
4.2.8. 6-(trifluoromethyl)-8-phenylphenanthridine (2h)
1
White solid, mp 126-127°C; H NMR (400 MHz, CDCl
3
): δ = 8.70 (d, J = 8.8 Hz,
1H), 8.33 (d, J = 8.4 Hz, 1H), 8.55-8.58 (m, 1H), 8.53 (s, 1H), 8.26-8.28 (m, 1H),
8
Page 8 of 22

1
3
8
.10-8.13 (m, 1H), 7.71-7.79 (m, 4H), 7.51-7.55 (m, 2H), 7.44-7.46 (m, 1H); C
NMR (100 MHz, CDCl ): δ = 146.6 (q, J = 32.7 Hz), 141.7, 140.9, 139.8, 132.9,
31.2, 130.7, 129.4, 129.3, 129.2, 128.3, 127.5, 125.0, 123.8 (q, J = 3.3 Hz), 123.1,
3
1
1
4
19
3
22.2, 122.1, 122.0 (q, J = 275.4 Hz). F NMR (376 MHz, CDCl ) δ -63.3 (s, 3 F).
[21]
.2.9. 6-(trifluoromethyl)-10-methylphenanthridine (2i)
1
White solid, mp 76-78°C; H NMR (400 MHz, CDCl
3
): δ 8.85-8.87 (m, 1H),
13
8
.30-8.34 (m, 2H), 7.75-7.83 (m, 3H), 7.66-7.69 (m, 1H), 3.15(s, 3H); C NMR (100
3
MHz, CDCl ): δ 147.1(q, J = 32.2 Hz), 142.8, 135.8, 135.6, 133.5, 131.5, 128.5,
128.4, 127.4, 126.6, 126.5, 124.3 (q, J = 3.6 Hz), 123.2, 122.1 (q, J =275.6 Hz), 27.1.
19
3
F NMR (376 MHz, CDCl ) δ -63.0 (s, 3 F).
[
21]
4.2.10. 6-(trifluoromethyl)-10-methoxyphenanthridine(2j)
1
White solid, mp 101-103°C; H NMR (500 MHz, CDCl
3
): δ 9.56-9.59 (m, 1H),
8
4
1
1
4
.29-8.32 (m, 1H), 8.03-8.05 (m, 1H), 7.72-7.82 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H),
13
.19 (s, 3H); C NMR (125 MHz, CDCl
3
): δ 158.3, 146.2 (q, J = 33.5 Hz), 142.3,
30.9, 129.1, 128.6, 128.2, 128.0, 125.0, 124.6, 123.8, 122.1 (q, J = 275.4 Hz), 118.0,
19
12.2, 55.9. F NMR (376 MHz, CDCl
3
) δ -63.4 (s, 3 F).
.2.11. 6-(trifluoromethyl)-7-methoxyphenanthridine(2k)
[
19]
and 6-(trifluoromethyl)-9-methoxyphenanthridine(2k´)
1
White solid. H NMR (400 MHz, CDCl
3
): δ 8.39 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 8.4
Hz, 0.69H), 8.16-7.20 (m, 2.2H), 8.07 (d, J = 8.0 Hz, 1H), 7.74-7.80 (m, 0.67H),
7
3
1
1
2
.64-7.73 (m, 4.32H), 7.21-7.24 (m, 0.63H), 7.03 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H),
13
3
.97 (s, 2H) ; C NMR (100 MHz, CDCl ): δ 161.6, 156.6, 146.0 (q, J = 32.5 Hz),
44.5 (q, J = 35.0Hz), 142.0, 141.4, 136.2, 136.1, 131.9, 130.9, 130.8, 129.3, 129.28,
29.0, 128.5, , 127.6 (q, J = 3.0 Hz), 124.7, 124.5, 122.4, 122.0, 122.0 (q, J =
73.2Hz), 122.0 (q, J = 275.2Hz), 118.4, 116.5, 114.4, 114.1, 109.1, 102.9, 56.0, 55.5.
19
3
F NMR (376 MHz, CDCl ) δ -63.23 (s, 2 F), -63.55 (s, 3 F).
[21]
4.2.12. 4-(trifluoromethyl)thieno[2,3-c]quinoline (2l)
1
White solid, mp 58-60°C; H NMR (400 MHz, CDCl
3
): δ 8.33 (d, J = 8.0 Hz, 1H),
13
8
3
.17-7.20 (m, 1H), 7.69-7.82 (m, 4H); C NMR (125 MHz, CDCl ): δ 147.9, 142.9(q,
9
Page 9 of 22

J = 34.6 Hz), 141.9, 131.0, 129.4, 129.1, 128.9, 127.5, 125.1, 123.3, 123.1 (q, J = 3.0
19
3
Hz), 121.8 (q, J = 274.9Hz). F NMR (376 MHz, CDCl ) δ -65.8 (s, 3 F).
[
22]
4.2.13. 6-(trifluoromethyl)-2-methylphenanthridine (2m)
1
White solid, mp 104-105°C; H NMR (400 MHz, CDCl
3
): δ 8.53 (d, J = 8.4 Hz, 1H),
8
7
.29 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.78-7.82 (m, 1H),
13
.65-7.69 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 2.59 (s, 3H); C NMR (100 MHz,
CDCl
25.7 (q, J = 3.0 Hz), 124.9, 122.4, 122.1 (q, J = 276.2Hz), 121.8, 12`1.6, 22.1. F
NMR (376 MHz, CDCl ) δ -63.3 (s, 3 F).
.2.14. 2-fluoro-6-(trifluoromethyl)phenanthridine(2n)
3
): δ 145.0(q, J = 32.5 Hz), 140.0, 139.5, 133.5, 131.05, 131.04, 130.7, 127.8,
19
1
3
[
20]
4
1
White solid, mp 104-106°C; H NMR (400 MHz, CDCl
3
): δ 8.44 (d, J = 8.4 Hz, 1H),
8
7
2
.33 (d, J = 8.4 Hz, 1H), 8.20-8.24 (m, 1H), 8.06-8.09 (m, 1H), 7.84-7.88 (m, 1H),
13
.73-7.77 (m, 1H), 7.46-7.51 (m, 1H); C NMR (100 MHz, CDCl
3
): δ 162.6 (d, J =
49.0 Hz), 145.8 (dq, J = 33.0, 2.8 Hz), 138.5, 133.5 (d, J = 9.5 Hz), 133.2 (d, J = 4.4
Hz), 131.4, 128.7, 126.7 (d, J = 9.6 Hz), 125.9 (q, J = 3.5 Hz), 122.6, 121.9 (q, J =
19
2
76.1 Hz), 121.7, 118.4 (d, J = 25.4 Hz), 107.1 (d, J = 23.7 Hz). F NMR (376 MHz,
CDCl ) δ -63.5 (s, 3 F), -108.7 (s, 1 F).
3
[22]
4.2.15. 3,6-bis(trifluoromethyl)phenanthridine(2o)
1
3
White solid, mp 105-107°C; H NMR (500 MHz, CDCl ): δ 8.63 (t, J = 8.5 Hz, 2H),
13
8
.61 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.92-7.98 (m, 2H), 7.82-7.85 (m, 1H); C
3
NMR (125 MHz, CDCl ): δ 147.9 (q, J = 33.4 Hz), 140.9, 133.1, 132.0, 131.2 (q, J =
33.2 Hz), 129.2, 128.6 (q, J = 3.4 Hz), 127.2, 126.1 (q, J = 3.4 Hz), 124.9 (q, J = 3.3
19
Hz), 123.7 (q, J = 270.9 Hz), 123.1, 122.8, 122.2, 121.6 (q, J = 275.1 Hz). F NMR
376 MHz, CDCl ) δ -62.5 (s, 3 F), -63.7 (s, 3 F).
(
3
[
20]
4.2.16. 6-(trifluoromethyl)-2,4-dimethylphenanthridine(2p)
1
White solid, mp 114-116°C; H NMR (400 MHz, CDCl
3
): δ 8.59 (d, J = 8.4 Hz, 1H),
8
2
.31-8.33 (m, 1H), 8.13 (s, 1H), 7.79-7.84 (m, 1H), 7.67-7.71 (m, 1H), 7.43 (s, 1H),
13
3
.81 (s, 3H), 2.56 (s, 3H); C NMR (100 MHz, CDCl ): δ 143.8 (q, J = 33.0 Hz),
10
Page 10 of 22

1
1
38.96, 138.91, 138.86, 133.9, 131.7, 130.7, 127.6, 125.6 (q, J = 3.4 Hz), 124.9, 122.7,
19
3
22.2 (q, J = 275.1Hz), 121.6, 119.4, 22.2, 17.9. F NMR (376 MHz, CDCl ) δ -63.3
(s, 3 F).
[
21]
4.2.17. 2,4-dichloro-6-(trifluoromethyl)phenanthridine(2q)
1
White solid, mp 120-122°C; H NMR (500 MHz, CDCl
3
): δ 8.36 (d, J = 8.5 Hz, 1H),
8
7
1
1
.29-8.31 (m, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.84-7.87 (m, 1H), 7.74-7.77 (m, 1H),
13
.73 (d, J = 2.5 Hz, 1H); C NMR (125 MHz, CDCl
3
): δ 146.7 (q, J = 33.6 Hz), 136.6,
36.5, 134.7, 132.5, 131.9, 129.9, 129.3, 127.0, 125.9 (q, J = 4.0 Hz), 122.6, 121.8,
19
3
21.6 (q, J = 270.3 Hz), 120.4. F NMR (376 MHz, CDCl ) δ -63.7 (s, 3 F).
4.2.18. 6-(perfluoroethyl)phenanthridine (2r)
1
White solid, mp 99-101°C; H NMR (400 MHz, CDCl
3
): δ 8.55 (d, J = 8.0 Hz, 1H),
13
8
.39-8.45 (m, 2H), 8.16-8.18 (m, 1H), 7.78-7.82 (m, 1H), 7.65-7.73 (m, 3H); C
3
NMR (100 MHz, CDCl ): δ 146.5(t, J = 26.3 Hz), 141.5, 133.8, 131.2, 131.1, 129.3,
19
1
29.2, 127.9, 125.9 (t, J = 6.8 Hz), 124.7, 122.5, 122.4, 121.9. F NMR (376 MHz,
3
CDCl ) δ -80.16 (s, 2 F), -106.80 (s, 3 F).
Acknowledgment
We are grateful to the National Natural Science Foundation of China (Project Nos.
U1204205; 21202078; 21272110)
References
[1] A. A. Ali, H. M. El Sayed, O. M. Abdallah, W. Steglich, Phytochemistry. 25 (1986)
2399-2401.
[
2] B. D. Krane, M. O. Fagbule, M. Shamma, J. Nat. Prod. 47 (1984) 1-43.
3] T. Nakanishi, M. Suzuki, A. Saimoto, T. Kabasawa, J. Nat. Prod. 62 (1999)
[
11
Page 11 of 22

8
64-867.
[4] T. Nakanishi, M. Suzuki, Org. Lett. 1 (1999) 985-988.
[
5] P. H. Bernardo, K.-F. Wan, T. Sivaraman, J. Xu, F. K. Moore, A. W. Hung, H. Y. K.
Mok, V. C. Yu, C. L. L. Chai, J. Med. Chem. 51 (2008) 6699-6710.
6] W. G. Lewis, L. G. Green, F. Grynszpan, Z. Radic, P. R. Carlier, P. Taylor, M. G.
Finn, K. B. Sharpless, Angew. Chem., Int. Ed. 41 (2002) 1053-1057.
7] E. Dubost, N. Dumas, C. Fossey, R. Magnelli, S. Butt-Gueulle, C. Balladonne, D.
H. Caignard, F. Dulin, J. S. d.-O. Santos, P. Millet, Y. Charnay, S. Rault, T. Cailly,
F. Fabis, J. Med. Chem. 55 (2012) 9693-9707.
[
[
[
8] J. Zhang, J. R. Lakowicz, J. Phys. Chem. B 109 (2005) 8701-8706.
9] S. L. Bondarev, V. N. Knyukshto, S. A. Tikhomirov, A. N. Pyrko, Opt. Spectrosc.
[
1
00 (2006) 386-393.
[
10] N. Stevens, N. O’Connor, H. Vishwasrao, D. Samaroo, E.R. Kandel, D.L. Akins,
C.M. Drain, N. J. Turro, J. Am. Chem. Soc. 130 (2008) 7182-7183.
[11] A. M. Linsenmeier, C. M. Williams, S. Brase, J. Org. Chem. 76 (2011)
̈
9
127-9132.
[
12] J. Peng, T. Chen, C. Chen, B. Li, J. Org. Chem. 76 (2011) 9507-9513.
13] L. Zhang, G. Y. Ang, S. Chiba, Org. Lett. 2010, 12, 3682-3685.
[
[14] Y. Wu, S. M. Wong, F. Mao, T. L. Chan, F. Y. Kwong, Org. Lett. 14 (2012)
5
306-5309.
[15] D. Intrieri, M. Mariani, A. Caselli, F. Ragaini, E. Gallo, Chem.-Eur. J. 18 (2012)
12
Page 12 of 22

1
0487-10490.
[
16] D. A. Candito, M. Lautens, Angew. Chem., Int. Ed. 48 (2009) 6713-6716.
17] F. Portela-Cubillo, E. M. Scanlan, J. S. Scott, J. C. Walton, Chem. Commun.
[
(2008) 4189-4191.
[
18] Y. Li, J. Zhu, L. Zhang, Y. Wu, Y. Gong, Chem.-Eur. J. 19 (2013) 8294-8299.
19] W.-Y. Wang, X. Feng, B.-L. Hu, C.-L. Deng, X.-G. Zhang, J. Org. Chem. 78
[
(2013) 6025-6030.
[
20] B. Zhang, C. Mück-Lichtenfeld, C. G. Daniliuc, A. Studer, Angew. Chem., Int.
Ed. 52 (2013) 10792-10795.
[21] Q. Wang, X. Dong, T. Xiao, L. Zhou, Org. Lett. 15 (2013) 4846-4849.
[22] Y. Cheng, H. Jiang, Y. Zhang, S. Yu, Org. Lett. 15 (2013) 5520-5523.
[23] K. Tamura, H. Mizukami, K. Maeda, H. Watanabe, K. Uneyama, J. Org. Chem.
5
8 (1993) 32-35.
[24] K. Uneyama, J. Fluorine Chem. 97 (1999) 11-25.
[
25] K. Uneyama, H. Amii, T. Katagiri, T. Kobayashi, T. Hosokawa, J. Fluorine
Chem. 126 (2005) 165-171.
[26] X. Dong, Y. Xu, J. Liu, Y. Hu, T. Xiao, L. Zhou, Chem.-Eur. J. 19 (2013)
16928-16933.
[
[
[
[
27] K. Uneyama, H. Watanabe, Tetrahedron Lett. 32 (1991) 1459-1462.
28] H. Amii, M. Kohda, M. Seo, K. Uneyama, Chem. Commun. (2003) 1752-1753.
29] C.-L. Li, M.-W. Chen, X.-G. Zhang, J. Fluorine Chem. 131 (2010) 856-860.
30] H. Amii, Y. Kishikawa, K. Kageyama, K. Uneyama, J. Org. Chem. 65 (2000)
13
Page 13 of 22

3
404-3408.
[31] H. Amii, K. Kageyama, Y. Kishikawa, T. Hosokawa, R. Morioka, T. Katagir, K.
Uneyama, Organometallics 31 (2012) 1281-1286.
[32] A. Isobe, J. Takagi, T. Katagiri, K. Uneyama, Org. Lett. 10 (2008) 2657-2659.
[33] D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 107 (2007) 174-238.
[34] E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola, Chem. Rev. 107
(2007) 5318-5365.
[
[
[
[
[
[
[
35] O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 42 (2009) 1074-1086.
36] B.-J. Li, Z.-J. Shi, Chem. Soc. Rev. 41 (2012) 5588-5598.
37] S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem. Soc. Rev. 40 (2011) 5068-5083.
38] S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 45 (2012) 936-946.
39] W. Fu, F. Xu, Y. Fu, C. Xu, S. Li, D. Zou, Eur. J. Org. Chem. (2014) 709-712.
40] M. Zhu, Z. Wang, F. Xu, J. Yu, W. Fu, J. Fluorine Chem. 156 (2013) 21-25.
41] M. Zhu, W. Fu, G. Zou, C. Xu, D. Deng, B. Ji, J. Fluorine Chem. 135 (2012)
1
95-199.
42] W. Fu, F. Xu, Y. Fu, M. Zhu, J. Yu, C. Xu, D. Zou, J. Org. Chem. 78 (2013)
2202-12206.
[
1
[
43] The atomic coordinates for 2r have been deposited at the Cambridge
Crystallographic Data Centre. CCDC ID: 986031 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
14
Page 14 of 22

[
44] C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res. 34 (2001) 633-64.
45] H. Amii, Y. Kishikawa, K. Uneyama, Org. Lett. 3 (2001) 1109-1112.
[
Scheme 1. Palladium-catalyzed intramolecular C−H bond functionalization of
trifluoroacetimidoyl chlorides
R2
R2
10 mol% Pd(PPh3)4
2
0 mol% PCy3
Cl
CF3
CF3
R1
2
.0 equiv. K CO
2
3
N
R1
N
o
toluene,120 C
2
1
15
Page 15 of 22

a
Table 1 Reactions of 1a under different conditions
Pd,base, ligand
Cl
CF3
o
solvent, 120 C
CF3
N
N
2a
1
a
b
Entry
Catalyst
Base
Ligand
Solvent Yield(%)
1
2
3
4
5
6
7
Pd(OAc)
2
K
K
K
K
K
K
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
PPh
PPh
PPh
PPh
3
3
3
3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
48
62
Pd(PPh )
3 4
Pd(PPh
3
)
2
Cl
2
38
Pd(CH CN)
3
2
Cl
2
trace
72
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
)
)
)
4
4
4
PCy
P(tBu)
PCy
3
3
64
K
3
PO
4
3
45
16
Page 16 of 22

8
9
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
3
3
)
4
)
4
)
4
)
4
)
4
)
4
Cs
2
CO
3
PCy
PCy
PCy
PCy
PCy
PCy
3
3
3
3
3
3
Toluene
Toluene
Toluene
DMF
54
37
Na
2
CO
3
1
0
KOAc
trace
43
1
1
2
3
K
2
K
2
K
2
CO
CO
CO
3
1
1
3
3
DMSO
trace
trace
3
CH CN
a
Reaction conditions:1a (0.4 mmol), [Pd] (10 mol%), Ligand (20 mol%), Base
(0.8 mmol) in solvent (4.0mL) at 120 °C under N
2
atmosphere for 12 h.
b
Isolated yield.
a
Table 2 Synthesis of 6-trifluoromethyl-phenanthridines
b
Entry
Substrate
Product
Yield (%)
1
2
3
4
5
6
7
R = H, 2b, 75
R = Et, 2c, 70
R
Cl
N
R = OCH , 2d, 67
R
3
CF3
R = F, 2e, 77
R = Cl, 2f, 69
N
CF
3
R = CF , 2g, 80
3
R = Ph, 2h, 62
R
R
8
9
R = CH , 2i, 58
3
Cl
N
N
CF
3
CF3
3
R = OCH , 2j, 51
17
Page 17 of 22

OCH3
P
OCH3
c
1
0
1
o
2k+2k' (o:p = 3:2) , 65
Cl
N
N
CF3
CF3
S
S
1
Cl
2l, 47
N
N
CF3
CF3
1
2
3
R
R = CH , 2m, 70
3
R
Cl
N
N
CF
3
1
CF3
R = F, 2n, 82
1
4
2o, 79
Cl
F3C
R
N
F
3
C
N
CF
3
CF3
1
5
6
R
R = CH , 2p, 65
3
Cl
CF
N
N
CF3
1
R
3
R = Cl, 2q, 76
R
1
7
Cl
CF CF3
2r, 74
N
N
2 3
CF CF
2
a
Reaction conditions:1a (0.4 mmol), Pd(PPh
CO (0.8 mmol) in toluene (4.0mL) at 120 °C under N
Isolated yield.
3
)
4
(10 mol%), PCy
3
(20 mol%),
K
2
3
2
atmosphere for 12 h.
b
c
19
The ratio of regioisomers based on F NMR analysis.
18
Page 18 of 22

Scheme 2. TEMPO-trapping experiment.
Pd(PPh ) , PCy
3
3
4
Cl
o
K CO , 120 C
CF3
2
3
N
N
CF3
TEMPO (1.2 equiv)
2a
1
a
70%
19
Page 19 of 22

Scheme 3. Plausible reaction mechanism.
Ar2
Ar2
Pd(II)Cl
CF3
Ar1
Ar1
Cl
N
N
Pd(0)
CF3
1
A
Ar2
Ar2
Ar1
Pd(II)
CF3
Ar1
CF3
N
N
2
B
20
Page 20 of 22

Figure 1. X-ray crystal structure of 2r
21
Page 21 of 22

Ar2
10 mol% Pd(PPh3)4
0 mol% PCy3
Ar2
N
2
Ar1
Cl
CF3
Ar1
CF3
N
2.0 ewquiv K CO
2
3
o
toluene,120 C
1
2
22
Page 22 of 22