Silver-Catalyzed Tandem Trifluoromethylation and Cyclization of Aryl Isonitriles with the Langlois Reagent

Article abstract of DOI:10.1055/s-0034-1378810

A mild and efficient procedure for the silver-catalyzed tandem trifluoromethylation and cyclization of aryl isonitriles with the Langlois reagent (sodium triflinate) is developed. A series of trifluoromethylated phenanthridines is prepared in moderate to good yields from a cheap and stable trifluoromethyl source.

Full text of DOI:10.1055/s-0034-1378810

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3460–3466
paper
3460
Y.-R. Liu et al.
Paper
Synthesis
Silver-Catalyzed Tandem Trifluoromethylation and Cyclization of
Aryl Isonitriles with the Langlois Reagent
Yu-Rong Liu
R2
R2
Hai-Yong Tu
AgNO3 (1 mol%)
TBHP (2 equiv)
Xing-Guo Zhang*
R1
R1
+
CF3SO2Na
Na2CO3 (1 equiv)
DMSO, 40 °C
N
CF3
NC
College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou 325027, P. R. of China
zxg@wzu.edu.cn
mild conditions
18 examples
32–85% yield
cheap and stable CF3 source
Received: 19.05.2015
Accepted after revision: 11.06.2015
Published online: 12.08.2015
Prakash reagent could also afford a trifluoromethyl radical,
which resulted in oxidative cyclization in the presence of
(diacetoxyiodo)benzene [PhI(OAc)2] (2.1 equiv) (Scheme 1,
eq 1, conditions d).9 However, the use of these expensive or
unstable trifluoromethylation reagents has limited the util-
ity and applicability of these reactions. As part of our ongo-
ing studies toward the preparation of trifluoromethylated
heterocycles,10 we herein report an efficient synthesis of 6-
(trifluoromethyl)phenanthridines through the silver-
catalyzed trifluoromethylation and cyclization of aryl
isonitriles with the Langlois reagent (sodium triflinate,
CF3SO2Na), a cheap and stable solid trifluoromethyl source
(Scheme 1, eq 2).11,12
DOI: 10.1055/s-0034-1378810; Art ID: ss-2015-f0321-op
Abstract A mild and efficient procedure for the silver-catalyzed tan-
dem trifluoromethylation and cyclization of aryl isonitriles with the
Langlois reagent (sodium triflinate) is developed. A series of trifluoro-
methylated phenanthridines is prepared in moderate to good yields
from a cheap and stable trifluoromethyl source.
Key words phenanthridines, trifluoromethylation, Langlois reagent-
cyclization
The phenanthridine structural unit can be found in nu-
merous natural products, for example, trisphaeridine and
nitidine,1 and potential pharmaceuticals with diverse bio-
logical activities, including antitumor, antiviral and anti-
fungal.2 Furthermore, substituted phenanthridines have
comprehensive applications in materials science due to
their optical and electronic properties.3 Therefore, various
methods have been developed for the construction of the
phenanthridine scaffold.4,5 Recently, the radical isonitrile
insertion reaction of 2-isocyanobiphenyls with radical pre-
cursors emerged as a versatile tool for the synthesis of 6-
substituted phenanthridines.5 Of these products, trifluoro-
methylated phenanthridines have received substantial at-
tention because the incorporation of a trifluoromethyl (CF3)
group into organic molecules can enhance their biological
activity and has become a powerful and widely used strate-
gy in drug design.6 For example, Studer and co-workers re-
ported the synthesis of 6-(trifluoromethyl)phenanthridines
via radical insertion reactions of isonitriles using Togni’s re-
agent or iodotrifluoromethane (CF3I) as trifluoromethyla-
tion reagents (Scheme 1, eq 1, conditions a and b).7 Yu and
co-workers also developed the trifluoromethylation of iso-
nitriles with Umemoto’s reagents (Scheme 1, eq 1, condi-
tions c).8 In addition, Zhou et al. found that the Ruppert–
(a) Togni's reagent
(b) CF3I
(1)
(c) Umemoto's reagents
(d) CF3SiMe3
N
CF3
NC
NC
Ag, TBHP
(2)
this work
+ CF3SO2Na
N
CF3
Scheme 1 Synthesis of 6-(trifluoromethyl)phenanthridines
Our preliminary studies were focused on the model re-
action of 2-isocyano-1,1′-biphenyl (1a) with sodium tri-
flinate in order to develop optimized conditions, and the re-
sults are summarized in Table 1. Initially, treatment of sub-
strate 1a with the Langlois reagent and tert-butyl
hydroperoxide (TBHP) at 40 °C in acetonitrile afforded the
desired product 2a in 48% yield (Table 1, entry 1). This re-
sult encouraged us to examine the use of metal catalysts
with the aim of increasing the reaction yield (Table 1, en-
tries 2–4). It was found that silver nitrate (AgNO3) was more
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3460–3466

3461
Y.-R. Liu et al.
Paper
Synthesis
effective than iron(III) chloride (FeCl3) and copper(I) bro-
mide (CuBr), and product 2a was isolated in 58% yield. In
view of the role of a base in deprotonation, we next investi-
gated the addition of some common bases (Table 1, entries
5–7). It was found that cesium acetate (CsOAc), potassium
carbonate (K2CO3) and sodium carbonate (Na2CO3) facilitat-
ed the reaction, with sodium carbonate providing product
2a in 84% yield. Further investigations disclosed that both
di-tert-butyl peroxide (DTBP) and potassium persulfate
(K2S2O8) were less effective than tert-butyl hydroperoxide
(Table 1, entries 8 and 9), whilst benzoyl peroxide (BPO)
was a completely ineffective oxidant for this reaction (Table
1, entry 10). During the examination of different solvents,
lower yields were observed when the reaction was carried
out in 1,2-dichloroethane (DCE), N,N-dimethylformamide
and toluene (Table 1, entries 11–13), however, the use of di-
methyl sulfoxide provided an 86% yield of 2a (Table 1, entry
14). It is noteworthy that almost the same yield (85%) was
obtained when the loading of silver nitrate was reduced to
1 mol% (Table 1, entry 15).
bearing either electron-donating or electron-withdrawing
substituents were suitable substrates, and were trans-
formed into the corresponding 6-(trifluoromethyl)phenan-
thridines in good yields. For example, 4-methyl- and
4-methoxy-substituted
isocyanobenzenes
afforded
phenanthridines 2b and 2c in 62% and 55% yields, respec-
tively, whilst isocyanides containing fluoro, chloro, or tri-
fluoromethyl groups gave products 2d–f in 61–76% yield.
Tolyl-substituted isocyanobenzenes 1g–i underwent
the reaction smoothly to afford the corresponding prod-
ucts, although poor regioselectivity was observed in the
case of 1i: two isomers, 2i and 2i′, were isolated in 33% and
21% yields, respectively. Methoxy-, fluoro-, chloro- and tri-
fluoromethylphenyl-substituted isocyanobenzenes were
well tolerated under the standard conditions to furnish
products 2j–n in 57–74% yields. A 2-isocyanobiphenyl bear-
ing two substituents (1o) was also converted successfully
into product 2o in 65% yield. Bulky 6-(trifluoromethyl)ben-
zo[k]phenanthridine (2p) was obtained in 32% yield from
the oxidative cyclization of 1-(2-isocyanophenyl)naphtha-
lene (1p). As expected, aryl isonitriles bearing a heterocy-
clic ring were also compatible in this transformation. For
example, thieno[3,2-c]quinoline 2q was prepared in 43%
yield. Benzonaphthyridines 2r and 2r′ were isolated in 41%
and 34% yields from the trifluoromethylation and cycliza-
tion of 3-(2-isocyanophenyl)pyridine (1r).
Table 1 Optimization of the Reaction Conditionsa
catalyst, oxidant
CF3SO2Na
+
base, solvent
To probe the reaction mechanism, we examined the re-
action of substrate 1a with the Langlois reagent under stan-
dard conditions in the presence of 2.5 equivalents of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a common
radical scavenger. The desired product 2a could not be de-
tected by TLC and GC–MS analysis, and almost 95% of reac-
tant 1a was recovered (Scheme 3). These results revealed
that the tandem reaction might involve a trifluoromethyl
radical pathway.
N
CF3
NC
1a
2a
Entry Cat.
Oxidant
Solvent
Base
Yield (%)
1
2
–
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
K2S2O8
BPO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
–
–
–
–
48
50
49
58
72
73
84
63
71
0
FeCl3
3
CuBr
4
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
Based on the above experimental results and previous
reports,7 a plausible mechanism is proposed in Scheme 4.
Firstly, a tert-butoxy radical is generated in situ from the
decomposition of tert-butyl hydroperoxide in the presence
of a trace amount of silver nitrate.12 Subsequently, the tert-
butoxy radical reacts with the Langlois reagent to provide a
trifluoromethyl radical along with the release of sulfur di-
oxide (SO2). Addition of the trifluoromethyl radical to 2-iso-
cyanobiphenyl 1a affords imidoyl radical intermediate A,
which is transformed into cyclohexadienyl radical B by in-
tramolecular electrophilic cyclization. Subsequent oxida-
tion of radical B produces cyclohexadienyl cation C through
a single electron transfer (SET) involving tert-butyl hydro-
5
CsOAc
6
K2CO3
7
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
8
9
10
11
12
13
14
15
TBHP
TBHP
TBHP
TBHP
TBHP
69
72
60
86
85
DMF
toluene
DMSO
DMSO
b
9
a Reaction conditions: 1a (0.2 mmol), CF3SO2Na (0.6 mmol), catalyst (5
mol%), oxidant (0.4 mmol), base (0.2 mmol), solvent (2 mL), 40 °C, N2 atm, 6
peroxide. Finally, deprotonation of intermediate C by the
base (Na2CO3) affords 6-(trifluoromethyl)phenanthridine
2a.
h.
b AgNO3 (1 mol%) was used.
In conclusion, we have developed a mild oxidative cy-
clization for the efficient synthesis of 6-(trifluorometh-
yl)phenanthridines that employs the cheap and stable
With the optimized reaction conditions established, we
subsequently investigated the substrate scope of the aryl
isonitriles (Scheme 2). In general, 2-isocyanobiphenyls
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3460–3466

3462
Y.-R. Liu et al.
Paper
Synthesis
R2
R2
AgNO3 (1 mol%)
TBHP (2 equiv)
+
R1
R1
CF3SO2Na
Na2CO3 (1 equiv)
DMSO, 40 °C
N
CF3
NC
1
2
Cl
Me
MeO
CF3
F
N
CF3
N
N
CF3
N
CF3
N
CF3
2a, 85%
2b, 62%
2c, 55%
2d, 61%
2e, 76%
Me
Me
Me
Me
CF3
F3C
N
CF3
N
CF3
N
CF3
Cl
N
N
CF3
2f, 64%
2g, 60%
2h, 62%
2i, 33% + 2i', 21%
CF3
F
OMe
MeO
N
CF3
N
CF3
N
CF3
N
CF3
N
CF3
2j, 63%
2k, 57%
2l, 74%
2m, 61%
2n, 66%
N
S
MeO
N
Cl
CF3
N
CF3
N
CF3
N
CF3
N
N
CF3
2o, 65%
2p, 32%
2q, 43%
2r, 41% + 2r', 34%
Scheme 2 Reactions of CF3SO2Na with different isocyanides. Reaction conditions: isocyanide 1a (0.2 mmol), CF3SO2Na (0.6 mmol), TBHP (0.4 mmol),
Na2CO3 (0.2 mmol), AgNO3 (1 mol%), DMSO (2 mL), 40 °C, 6 h, N2 atm. Yields are those of isolated products.
Ag+
TEMPO (2.5 equiv)
standard conditions
1a
CF3SO2Na
SO2
CF3SO2Na
2a
t-BuOOH
•CF3
t-BuO
•
+
•
N
CF3
not detected
OH–
NC
A
1a
95% of 1a was recovered
Scheme 3 A control experiment
+
•
t-BuOOH
Na2CO3
H+
H
CF3
SET
H
N
N
CF3
N
CF3
B
C
Langlois reagent. In the presence of silver nitrate (1 mol%),
tert-butyl hydroperoxide, and sodium carbonate, a wide va-
riety of aryl isonitriles were transformed into the corre-
sponding phenanthridines, in moderate to good yields, via a
tandem trifluoromethylation–cyclization process. The pres-
ent procedure might prove useful for the convenient syn-
thesis of other trifluoromethylated heterocycles.
2a
Scheme 4 A possible mechanism
Chemicals were either purchased or were purified by standard tech-
niques. All reactions under a nitrogen atmosphere were conducted
using standard Schlenk techniques. Column chromatography was per-
formed using EM Silica gel 60 (300–400 mesh). Petroleum ether (PE)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3460–3466

3463
Y.-R. Liu et al.
Paper
Synthesis
refers to the fraction boiling in the 60–90 °C range. Melting points
were obtained using a TAIRON 4-X digital display microscopic melting
point detector. IR spectra were recorded using a Nicolet iS10 spectro-
13C NMR (125 MHz, CDCl3): δ = 160.0, 143.7 (q, J = 32.7 Hz), 136.8,
133.1, 132.4, 130.7, 128.0, 126.4, 125.6, 122.4, 122.1 (q, J = 275.0 Hz),
121.8, 119.3, 102.6, 55.6.
1
photometer. H (500 MHz) and 13C NMR (125 MHz) spectra were re-
19F NMR (470 MHz, CDCl3): δ = –63.1 (3 F).
corded at room temperature on a Bruker Avance-III 500 MHz spec-
trometer, using CDCl3 as the solvent and tetramethylsilane (TMS) as
an internal standard. Chemical shifts (δ) are quoted relative to TMS,
and the coupling constants (J) are given in Hz. 19F NMR (470 MHz)
spectra were recorded on the same instrument and are reported rela-
tive to CFCl3 as the internal standard. Low-resolution mass spectra
were recorded using a Shimadzu GC-MS-QP2010 Plus mass spec-
trometer. High-resolution mass spectra were obtained using a Bruker
micrOTOF-QII mass spectrometer.
MS (EI, 70 eV): m/z (%) = 277 (100) [M]+, 262 (15), 234 (51), 184 (32),
164 (9).
HRMS (ESI): m/z [M + H]+ calcd for C15H11F3NO: 278.0787; found:
278.0793.
2-Fluoro-6-(trifluoromethyl)phenanthridine (2d)10
Yield: 32.4 mg (61%); gray solid; mp 115–117 °C.
IR (neat): 1620, 1172, 1130, 973, 864, 770 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.29–8.27 (m, 1 H), 8.19 (d, J = 8.0 Hz, 1
H), 8.09–8.06 (m, 1 H), 7.92–7.89 (m, 1 H), 7.73–7.70 (m, 1 H), 7.63–
7.60 (m, 1 H), 7.36–7.32 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 162.6 (d, J = 249.3 Hz), 145.8 (q, J =
33.0 Hz), 138.5, 133.5, 133.3, 131.3, 128.7, 126.7, 125.9, 123.0, 122.6,
121.9 (q, J = 275.3 Hz), 118.4 (d, J = 24.4 Hz), 107.1 (d, J = 23.5 Hz).
6-(Trifluoromethyl)phenanthridines; General Procedure
A mixture of 2-isocyano-1,1′-biphenyl 1 (0.2 mmol), CF3SO2Na (93.6
mg, 0.6 mmol), AgNO3 (0.33 mg, 1 mol%), TBHP (0.4 mmol, 36.0 mg)
and Na2CO3 (21.2 mg, 0.2 mmol) in DMSO (2 mL) was stirred at 40 °C
under an N2 atm for 6 h, or until complete consumption of the start-
ing material as monitored by TLC or GC–MS analysis. After the reac-
tion was complete, the mixture was poured into EtOAc (10 mL) and
evaporated under vacuum. The residue was purified by flash column
chromatography (PE–EtOAc) to afford the desired product 2a–r.
19F NMR (470 MHz, CDCl3): δ = –63.5 (s, 3 F), –108.8 (s, 1 F).
MS (EI, 70 eV): m/z (%) = 265 (100) [M]+, 196 (67), 176 (8), 169 (18),
138 (19).
6-(Trifluoromethyl)phenanthridine (2a)10
2-Chloro-6-(trifluoromethyl)phenanthridine (2e)10
Yield: 42.0 mg (85%); yellow solid; mp 72–74 °C.
Yield: 42.7 mg (76%); yellow solid; mp 118–120 °C.
IR (neat): 1613, 1179, 1115, 759, 719 cm–1
.
IR (neat): 1610, 1179, 1124, 830, 768 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.67 (d, J = 8.5 Hz, 1 H), 8.57 (d, J = 7.5
Hz, 1 H), 8.37 (d, J = 8.5 Hz, 1 H), 8.27 (d, J = 7.5 Hz, 1 H), 7.91–7.88 (m,
1 H), 7.80–7.73 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 146.5 (q, J = 32.8 Hz), 141.8, 134.0,
131.3, 131.1, 129.3, 129.2, 128.0, 125.9, 125.1, 122.5, 122.04, 121.96
(q, J = 275.4 Hz), 121.8.
1H NMR (500 MHz, CDCl3): δ = 8.47 (d, J = 8.0 Hz, 1 H), 8.41 (s, 1 H),
8.27 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.5 Hz, 1 H), 7.84–7.81 (m, 1 H),
7.71–7.68 (m, 1 H), 7.63 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 146.7 (q, J = 33.0 Hz), 140.1, 135.4,
132.8, 132.5, 131.6, 129.9, 128.7, 126.1, 125.9, 122.5, 121.9, 121.75 (q,
J = 275.5 Hz), 121.71.
19F NMR (470 MHz, CDCl3): δ = –63.4 (3 F).
MS (EI, 70 eV): m/z (%) = 247 (100) [M]+, 178 (69), 151 (31), 123 (6),
19F NMR (470 MHz, CDCl3): δ = –63.6 (3 F).
MS (EI, 70 eV): m/z (%) = 281 (100) [M]+, 213 (38), 177 (54), 150 (10),
75 (6).
123 (6).
2-Methyl-6-(trifluoromethyl)phenanthridine (2b)10
3,6-Bis(trifluoromethyl)phenanthridine (2f)8
Yield: 32.4 mg (62%); brown solid; mp 103–105 °C.
Yield: 40.3 mg (64%); white solid; mp 105–108 °C.
IR (neat): 1630, 1338, 1158, 1119, 775, 727 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.63–8.59 (m, 2 H), 8.49 (s, 1 H), 8.33
(d, J = 8.5 Hz, 1 H), 7.92–7.87 (m, 2 H), 7.79–7.75 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 148.0 (q, J = 33.3 Hz), 141.1, 133.3,
132.0, 131.3 (q, J = 33.1 Hz), 129.3, 128.7, 127.3, 126.2, 125.0, 123.8
(q, J = 270.8 Hz), 123.2, 122.9, 122.4, 121.7 (q, J = 275.6 Hz).
IR (neat): 1616, 1174, 1118, 827, 770 cm–1
.
.
1H NMR (500 MHz, CDCl3): δ = 8.64 (d, J = 8.5 Hz, 1 H), 8.35–8.33 (m, 2
H), 8.15 (d, J = 8.5 Hz, 1 H), 7.88–7.85 (m, 1 H), 7.74–7.71 (m, 1 H),
7.60 (d, J = 8.5 Hz, 1 H), 2.64 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 145.5 (q, J = 32.6 Hz), 140.1, 139.5,
133.7, 131.1, 131.0, 130.8, 127.8, 125.8, 125.2, 122.5, 122.1 (q, J =
275.3 Hz), 121.9, 121.6, 22.1.
19F NMR (500 MHz, CDCl3): δ = –62.5 (3 F), –63.7 (3 F).
MS (EI, 70 eV): m/z (%) = 315 (100) [M]+, 246 (63), 226 (32), 177 (24),
19F NMR (470 MHz, CDCl3): δ = –63.3 (3 F).
MS (EI, 70 eV): m/z (%) = 261 (100) [M]+, 241 (32), 192 (19), 165 (15),
123 (5).
95 (10).
8-Methyl-6-(trifluoromethyl)phenanthridine (2g)9
2-Methoxy-6-(trifluoromethyl)phenanthridine (2c)
Yield: 31.3 mg (60%); brown solid; mp 101–103 °C.
Yield: 30.5 mg (55%); brown solid; mp 93–95 °C.
IR (neat): 1609, 1175, 1119, 826, 769 cm–1
.
IR (neat): 1620, 1166, 1100, 824, 761 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.51–8.49 (m, 2 H), 8.19 (d, J = 7.5 Hz, 1
H), 8.06 (s, 1 H), 7.70–7.66 (m, 3 H), 2.55 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 146.2 (q, J = 32.5 Hz), 141.5, 138.2,
133.2, 131.9, 131.1, 129.1, 128.9, 125.24, 125.21, 122.4, 121.97 (q, J =
273.1 Hz), 121.96, 121.8, 21.9.
1H NMR (500 MHz, CDCl3): δ = 8.44 (d, J = 8.0 Hz, 1 H), 8.23 (d, J = 8.0
Hz, 1 H), 8.07 (d, J = 9.0 Hz, 1 H), 7.76–7.73 (m, 2 H), 7.64–7.61 (m, 1
H), 7.29 (d, J = 9.0 Hz, 1 H), 3.92 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3460–3466

3464
Y.-R. Liu et al.
Paper
Synthesis
19F NMR (470 MHz, CDCl3): δ = –63.5 (3 F).
MS (EI, 70 eV): m/z (%) = 261 (100) [M]+, 241 (31), 190 (17), 165 (15),
10-Methoxy-6-(trifluoromethyl)phenanthridine (2k)9
Yield: 31.6 mg (57%); yellow solid; mp 103–105 °C.
IR (neat): 1573, 1276, 1177, 1121, 776, 720 cm–1
96 (10).
.
1H NMR (500 MHz, CDCl3): δ = 9.54 (d, J = 8.0 Hz, 1 H), 8.28 (d, J = 7.5
Hz, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.78–7.75 (m, 2 H), 7.71–7.68 (m, 1
H), 7.37 (d, J = 8.0 Hz, 1 H), 4.15 (s, 3 H).
10-Methyl-6-(trifluoromethyl)phenanthridine (2h)9
Yield: 32.4 mg (62%); yellow solid; mp 90–92 °C.
IR (neat): 1660, 1166, 1133, 761, 737 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.61–8.57 (m, 2 H), 8.28–8.26 (m, 1 H),
.
13C NMR (125 MHz, CDCl3): δ = 158.3, 146.2 (q, J = 32.4 Hz), 142.2,
130.9, 129.0, 128.5, 128.2, 128.0, 125.0, 124.5, 123.8, 122.1 (d, J =
275.5 Hz), 118.0, 112.2, 55.9.
19F NMR (470 MHz, CDCl3): δ = –63.3 (3 F).
MS (EI, 70 eV): m/z (%) = 277 (100) [M]+, 262 (29), 242 (52), 184 (12),
8.14 (s, 1 H), 7.80–7.75 (m, 3 H), 2.64 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 146.2 (q, J = 32.0 Hz), 141.4, 138.2,
133.2, 131.9, 131.0, 129.1, 128.9, 125.3, 125.2, 122.4, 121.963,
121.957 (q, J = 273.1 Hz), 121.9, 21.9.
139 (15).
19F NMR (470 MHz, CDCl3): δ = –63.5 (3 F).
MS (EI, 70 eV): m/z (%) = 261 (100) [M]+, 241 (8), 192 (28), 165 (19),
8-Chloro-6-(trifluoromethyl)phenanthridine (2l)7
Yield: 41.6 mg (74%); white solid; mp 107–109 °C.
131(5).
1H NMR (500 MHz, CDCl3): δ = 8.54–8.52 (m, 1 H), 8.47–8.46 (m, 1 H),
8.28 (s, 1 H), 8.24 (d, J = 7.0 Hz, 1 H), 7.81–7.60 (m, 3 H).
7-Methyl-6-(trifluoromethyl)phenanthridine (2i)10
13C NMR (125 MHz, CDCl3): δ = 145.4 (q, J = 32.0 Hz), 141.7, 134.3,
132.3, 132.0, 131.2, 129.65, 129.63, 125.2, 124.7, 124.2, 122.5, 121.9,
121.6 (q, J = 275.4 Hz).
Yield: 17.2 mg (33%); brown solid; mp 44–46 °C.
IR (neat): 1607, 1171, 1119, 963, 763 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.62–8.57 (m, 2 H), 8.25–8.23 (m, 1 H),
7.80–7.74 (m, 3 H), 7.61 (d, J = 7.5 Hz, 1 H), 2.93 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 145.1 (q, J = 33.1 Hz), 140.7, 135.9,
135.6, 132.7, 130.7, 130.5, 129.2, 129.1, 125.4, 122.4, 122.3, 122.0 (q,
J = 274.0 Hz), 120.8, 23.4.
19F NMR (470 MHz, CDCl3): δ = –63.6 (3 F).
IR (neat): 1610, 1184, 1174, 1112, 983, 760 cm–1
.
MS (EI, 70 eV): m/z (%) = 281 (100) [M]+, 212 (42), 177 (61), 150 (13),
123 (6).
19F NMR (470 MHz, CDCl3): δ = –59.8 (3 F).
MS (EI, 70 eV): m/z (%) = 261 (100) [M]+, 241 (7), 192 (35), 177 (10),
8-Fluoro-6-(trifluoromethyl)phenanthridine (2m)5e
Yield: 32.3 mg (61%); yellow solid; mp 84–86 °C.
165 (22).
IR (neat): 1627, 1166, 1120, 766, 737 cm–1
.
9-Methyl-6-(trifluoromethyl)phenanthridine (2i′)10
1H NMR (500 MHz, CDCl3): δ = 8.69–8.66 (m, 1 H), 8.53–8.52 (m, 1 H),
8.28–8.27 (m, 1 H), 7.99 (d, J = 9.5 Hz, 1 H), 7.80–7.79 (m, 2 H), 7.68–
7.65 (m, 1 H).
Yield: 11.0 mg (21%); yellow solid; mp 67–69 °C.
IR (neat): 1620, 1174, 1119, 971, 759 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 161.5 (d, J = 248.6 Hz), 145.7 (q, J =
33.1 Hz), 141.5, 131.3, 130.7, 129.7, 129.2, 125.2, 124.7, 122.9, 121.8,
120.8 (d, J = 24.0 Hz), 121.7 (q, J = 275.4 Hz), 110.8 (d, J = 23.1 Hz).
19F NMR (470 MHz, CDCl3): δ = –64.0 (3 F), –109.9 (1 F).
MS (EI, 70 eV): m/z (%) = 265 (100) [M]+, 196 (67), 176 (9), 169 (26),
1H NMR (500 MHz, CDCl3): δ = 8.54 (d, J = 7.5 Hz, 1 H), 8.42 (s, 1 H),
8.20 (d, J = 7.5 Hz, 2 H), 7.74–7.70 (m, 2 H), 7.53 (d, J = 8.5 Hz, 1 H),
2.66 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 146.4 (q, J = 32.8 Hz), 142.1, 141.9,
134.2, 131.1, 129.8, 129.2, 128.9, 125.8, 125.0, 122.12, 122.05, 122.03
(q, J = 275.4 Hz), 119.9, 22.3.
133 (8).
19F NMR (470 MHz, CDCl3): δ = –63.5 (3 F).
MS (EI, 70 eV): m/z (%) = 261 (100) [M]+, 241 (11), 192 (40), 165 (33),
6,8-Bis(trifluoromethyl)phenanthridine (2n)9
Yield: 41.6 mg (66%); yellow solid; mp 104–107 °C.
121 (7).
IR (neat): 1627, 1324, 1168, 1124, 764 cm–1
.
8-Methoxy-6-(trifluoromethyl)phenanthridine (2j)9
1H NMR (500 MHz, CDCl3): δ = 8.77 (d, J = 8.5 Hz, 1 H), 8.62 (s, 1 H),
8.59–8.57 (m, 1 H), 8.30–8.29 (m, 1 H), 8.08 (d, J = 8.5 Hz, 1 H), 7.89–
7.81 (m, 2 H).
Yield: 34.9 mg (63%); white solid; mp 101–103 °C.
IR (neat): 1623, 1169, 1131, 765, 735 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 146.4 (q, J = 33.4 Hz), 142.4, 136.0,
131.4, 130.5, 130.3 (q, J = 33.4 Hz), 129.9, 127.2, 124.1, 123.71, 123.65
(q, J = 270.9 Hz), 123.4, 122.6, 121.6 (q, J = 275.3 Hz), 121.1.
19F NMR (470 MHz, CDCl3): δ = –62.6 (3 F), –63.3 (3 F).
MS (EI, 70 eV): m/z (%) = 315 (100) [M]+, 296 (12), 246 (57), 226 (32),
1H NMR (500 MHz, CDCl3): δ = 8.59 (d, J = 9.0 Hz, 1 H), 8.51 (d, J = 9.0
Hz, 1 H), 8.26 (d, J = 9.0 Hz, 1 H), 7.77–7.73 (m, 2 H), 7.67 (s, 1 H), 7.54
(d, J = 9.0 Hz, 1 H), 4.00 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 159.0, 145.5 (d, J = 32.4 Hz), 141.0,
131.1, 129.2, 128.5, 128.3, 125.3, 124.1, 123.2, 122.5, 122.0 (q, J =
273.2 Hz), 121.6, 105.6, 55.6.
207 (10), 177 (22).
19F NMR (470 MHz, CDCl3): δ = –64.1 (3 F).
7-Chloro-10-methoxy-6-(trifluoromethyl)phenanthridine (2o)
MS (EI, 70 eV): m/z (%) = 277 (100) [M]+, 234 (74), 207 (12), 184 (16),
Yield: 40.5 mg (65%); white solid; mp 123–125 °C.
164 (9).
IR (neat): 1587, 1164, 1141, 994, 761 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3460–3466

3465
Y.-R. Liu et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 9.44 (d, J = 8.5 Hz, 1 H), 8.22 (d, J = 8.0
Hz, 1 H), 7.79–7.76 (m, 1 H), 7.72 (d, J = 8.5 Hz, 2 H), 7.23 (d, J = 8.5 Hz,
1 H), 4.12 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.9, 143.7 (q, J = 34.4 Hz), 141.3,
131.3, 130.4, 129.4, 129.2, 127.5, 127.3, 123.9, 122.3, 121.6 (q, J =
274.3 Hz), 122.0, 112.0, 56.1.
IR (neat): 1566, 1180, 1116, 770, 718 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.19 (s, 1 H), 8.97–8.96 (m, 1 H),
8.79–8.77 (m, 1 H), 8.38–8.36 (m, 1 H), 8.15–8.14 (m, 1 H), 7.93–7.91
(m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 147.3, 146.5, 145.6 (q, J = 30.3 Hz),
142.4, 131.6, 130.7, 130.4, 127.5, 125.0, 123.3, 121.5, 121.4 (q, J =
276.3 Hz), 117.6.
19F NMR (470 MHz, CDCl3): δ = –58.3 (3 F).
MS (EI, 70 eV): m/z (%) = 311 (100) [M]+, 296 (38), 276 (48), 207 (39),
19F NMR (470 MHz, CDCl3): δ = –64.2 (3 F).
164 (25).
MS (EI, 70 eV): m/z (%) = 248 (100) [M]+, 179 (64), 152 (30), 125 (15),
99 (7).
HRMS (ESI): m/z [M + H]+ calcd for C15H10F3NOCl: 312.0398; found:
312.0397.
HRMS (ESI): m/z [M + H]+ calcd for C13H8F3N2: 249.0634; found:
249.0632.
6-(Trifluoromethyl)benzo[k]phenanthridine (2p)
Yield: 19.0 mg (32%); yellow solid; mp 53–55 °C.
IR (neat): 1630, 1173, 1117, 754, 730 cm–1
.
Acknowledgment
1H NMR (500 MHz, CDCl3): δ = 9.13–9.12 (m, 1 H), 9.06 (d, J = 8.0 Hz, 1
H), 8.42 (d, J = 8.0 Hz, 1 H), 8.26 (d, J = 9.0 Hz, 1 H), 8.10–8.09 (m, 1 H),
8.05 (d, J = 9.0 Hz, 1 H), 7.87–7.83 (m, 2 H), 7.80–7.78 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 145.7 (q, J = 32.2 Hz), 143.8, 134.7,
133.7, 130.9, 129.2, 129.0, 128.8, 128.72, 128.68, 128.62, 128.5, 127.3,
127.2, 125.4, 122.3 (q, J = 273.2 Hz), 121.3, 121.0.
We thank the National Natural Science Foundation of China (No.
21272177) and Zhejiang Provincial Natural Science Foundation of
China (No. LR15B020002) for financial support.
Supporting Information
19F NMR (470 MHz, CDCl3): δ = –62.5 (3 F).
MS (EI, 70 eV): m/z (%) = 297 (100) [M]+, 276 (23), 228 (23), 201 (15),
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378810.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
100 (16).
HRMS (ESI): m/z [M + H]+ calcd for C18H11F3N: 298.0838; found:
298.0846.
References
(1) (a) Giordani, R. B.; de Andrade, J. P.; Verli, H.; Dutilh, J. H.;
Henriques, A. T.; Berkov, S.; Bastid, J.; Zuanazzia, J. A. S. Magn.
Reson. Chem. 2011, 49, 668. (b) Abdel-Halim, O. B.; Morikawa,
T.; Ando, S.; Matsuda, H.; Yoshikawa, M. J. Nat. Prod. 2004, 67,
1119. (c) Tsai, I. L.; Wun, M. F.; Teng, C. M.; Ishikawa, T.; Chen, I.
S. Phytochemistry 1998, 48, 1377. (d) Fang, S.-D.; Wang, L.-K.;
Hecht, S. M. J. Org. Chem. 1993, 58, 5025.
(2) (a) Ishikawa, T. Med. Res. Rev. 2001, 21, 61. (b) Denny, W. A.
Curr. Med. Chem. 2002, 9, 1655. (c) Zhu, S.; Ruchelman, A. L.;
Zhou, N.; Liu, A.; Liu, L. F.; Lavoie, E. J. Bioorg. Med. Chem. 2005,
13, 6782. (d) 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. (e) Dubost, E.; Dumas, N.; Fossey,
C.; Magnelli, R.; Butt-Gueulle, S.; Ballandonne, C.; Caignard, D.
H.; Dulin, F.; de-Oliveira Santos, J. S.; Millet, P.; Charnay, Y.;
Rault, S.; Cailly, T.; Fabis, F. J. Med. Chem. 2012, 55, 9693.
(3) (a) Zhang, J.; Lakowicz, J. R. J. Phys. Chem. B 2005, 109, 8701.
(b) Bondarev, S. L.; Knyukshto, V. N.; Tikhomirov, S. A.; Pyrko, A.
N. Opt. Spectrosc. 2006, 100, 386. (c) Stevens, N.; O’Connor, N.;
Vishwasrao, H.; Samaroo, D.; Kandel, E. R.; Akins, D. L.; Drain, C.
M.; Turro, N. J. J. Am. Chem. Soc. 2008, 130, 7182.
(4) (a) Read, M. L.; Gundersen, L.-L. J. Org. Chem. 2013, 78, 1311.
(b) Intrieri, D.; Mariani, M.; Caselli, A.; Ragaini, F.; Gallo, E.
Chem. Eur. J. 2012, 18, 10487. (c) Linsenmeier, A. M.; Williams,
C. M.; Brase, S. J. Org. Chem. 2011, 76, 9127. (d) Peng, J.; Chen, T.;
Chen, C.; Li, B. J. Org. Chem. 2011, 76, 9507. (e) Zhang, L.; Ang, G.
Y.; Chiba, S. Org. Lett. 2010, 12, 3682. (f) Candito, D. A.; Lautens,
M. Angew. Chem. Int. Ed. 2009, 48, 6713. (g) Gerfaud, T.;
Neuville, L.; Zhu, J. Angew. Chem. Int. Ed. 2009, 48, 572.
(h) Portela-Cubillo, F.; Scanlan, E. M.; Scott, J. S.; Walton, J. C.
Chem. Commun. 2008, 4189.
4-(Trifluoromethyl)thieno[3,2-c]quinoline (2q)9
Yield: 21.8 mg (43%); yellow solid; mp 59–61 °C.
IR (neat): 1643, 1184, 1118, 759, 711 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.33 (d, J = 8.0 Hz, 1 H), 8.18 (d, J = 8.0
Hz, 1 H), 7.81–7.78 (m, 2 H), 7.75–7.72 (m, 1 H), 7.70–7.69 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 147.8, 142.9 (q, J = 31.0 Hz), 141.9,
131.1, 129.4, 129.1, 129.0, 127.4, 125.1, 123.2, 123.1, 121.8 (q, J =
274.5 Hz).
19F NMR (470 MHz, CDCl3): δ = –65.7 (3 F).
MS (EI, 70 eV): m/z (%) = 253 (100) [M]+, 184 (44), 140 (37), 127 (6),
113 (8).
5-(Trifluoromethyl)benzo[f][1,7]naphthyridine (2r)
Yield: 20.4 mg (41%); white solid; mp 112–114 °C.
IR (neat): 1580, 1180, 1131, 986, 764 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.17–9.16 (m, 1 H), 8.97 (d, J = 8.5 Hz, 1
H), 8.56 (d, J = 8.0 Hz, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 7.90–7.84 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 150.8, 147.5 (q, J = 32.3 Hz), 141.7,
138.7, 131.4, 130.4, 130.1, 129.7, 129.3, 125.7, 124.6, 122.1, 121.6 (q,
J = 275.8 Hz).
19F NMR (470 MHz, CDCl3): δ = –64.3 (3 F).
MS (EI, 70 eV): m/z (%) = 248 (100) [M]+, 179 (94), 152 (39), 125 (16),
91 (12).
HRMS (ESI): m/z [M + H]+ calcd for C13H8F3N2: 249.0634; found:
249.0637.
5-(Trifluoromethyl)benzo[c][2,6]naphthyridine (2r′)
Yield: 16.9 mg (34%); yellow solid; mp 159–161 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3460–3466

3466
Y.-R. Liu et al.
Paper
Synthesis
(5) For selected examples, see: (a) Wang, L.; Sha, W.; Dai, Q.; Feng,
X.; Wu, W.; Peng, H.; Chen, B.; Cheng, J. Org. Lett. 2014, 16, 2088.
(b) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.; Zhang, Y.; Yu, S.
Angew. Chem. Int. Ed. 2013, 52, 13289. (c) Zhang, B.; Daniliuc, C.
G.; Studer, A. Org. Lett. 2014, 16, 250. (d) Liu, J.; Fan, C.; Yin, H.;
Qin, C.; Zhang, G.; Zhang, X.; Yi, H.; Lei, A. Chem. Commun. 2014,
50, 2145. (e) Fu, W.-J.; Zhu, M.; Xu, F.-J.; Fu, Y.-Q.; Xua, C.; Zou,
D.-P. RSC Adv. 2014, 4, 17226.
(6) For selected examples, see: (a) Müller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, 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.
(7) (a) Zhang, B.; Mück-Lichtenfeld, C.; Daniliuc, C. G.; Studer, A.
Angew. Chem. Int. Ed. 2013, 52, 10792. (b) Zhang, B.; Studer, A.
Org. Lett. 2014, 16, 3990.
(8) (a) Cheng, Y.; Jiang, H.; Zhang, Y.; Yu, S. Org. Lett. 2013, 15, 5520.
(b) Wang, R.-Z.; Jiang, H.; Cheng, Y.-Z.; Kadi Adnan, A.; Fun, H.-
K.; Zhang, Y.; Yu, S.-Y. Synthesis 2014, 46, 2711.
(9) Wang, Q.-L.; Dong, X.-C.; Xiao, T.-B.; Zhou, L. Org. Lett. 2013, 15,
4846.
(10) Wang, W.-Y.; Sun, L.-L.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G.
J. Org. Chem. 2013, 78, 6025.
(11) (a) Wei, W.; Wen, J.-W.; Yang, D.-S.; Liu, X.-X.; Guo, M.-Y.; Dong,
R.-M.; Wang, H. J. Org. Chem. 2014, 79, 4225. (b) Langlois, B. R.;
Laurent, E.; Roidot, N. Tetrahedron Lett. 1991, 32, 7525. (c) Ye, Y.
D.; Kuenzi, S. A.; Sanford, M. S. Org. Lett. 2012, 14, 4979. (d) Li, Z.
J.; Cui, Z. L.; Liu, Z. Q. Org. Lett. 2013, 15, 406. (e) Presset, M.;
Oehlrich, D.; Rombouts, F.; Molander, G. A. J. Org. Chem. 2013,
78, 12837. (f) Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.;
Maiti, D. Angew. Chem. Int. Ed. 2013, 52, 9747. (g) Yang, F.;
Klumphu, P.; Liang, Y.-M.; Lipshutz, B. H. Chem. Commun. 2014,
50, 936.
(12) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;
Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011,
108, 14411.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3460–3466