Synthesis of 6-(trifluoromethyl)phenanthridines via palladium-catalyzed tandem Suzuki/C-H arylation reactions

Article abstract of DOI:10.1021/jo4007255

A palladium-catalyzed tandem Suzuki/C-H arylation reaction of N-aryltrifluoroacetimidoyl chlorides with arylboronic acids has been developed. A variety of 6-(trifluoromethyl)phenanthridines were prepared in moderate to excellent yields from N-(2-bromophenyl)trifluoroacetimidoyl chlorides which can be conveniently prepared from 2-bromoaniline derivatives.

Full text of DOI:10.1021/jo4007255

Article
pubs.acs.org/joc
Synthesis of 6‑(Trifluoromethyl)phenanthridines via Palladium-
Catalyzed Tandem Suzuki/C−H Arylation Reactions
Wen-Ying Wang, Xia Feng, Bo-Lun Hu, Chen-Liang Deng, and Xing-Guo Zhang*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed tandem Suzuki/C−H
arylation reaction of N-aryltrifluoroacetimidoyl chlorides with
arylboronic acids has been developed. A variety of 6-
(trifluoromethyl)phenanthridines were prepared in moderate
to excellent yields from N-(2-bromophenyl)-
trifluoroacetimidoyl chlorides which can be conveniently prepared from 2-bromoaniline derivatives.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The reaction of N-(2-bromophenyl)-2,2,2-trifluoroacetimidoyl
chloride 1a with phenylboronic acid 2a was used as a model
reaction to screen the optimal reaction conditions, and the
results are summarized in Table 1. Initially, treatment of
substrate 1a with phenylboronic acid, Pd(OAc)2 (10 mol %),
K2CO3 (2 equiv), PPh3, and Ag2CO3 in toluene at 120 °C
afforded the desired product 3 in 49% yield (entry 1). Further
investigation into catalysts demonstrated that Pd(0) was more
effective than Pd(II) species, and the reaction yield increased to
73% using Pd(PPh3)4 as catalyst (entries 1−4). Some bulky
phosphine ligands such as XPhos, SPhos, and RuPhos were
examined with the aim of increasing the reaction yield, but all
were less effective than PPh3 (entries 5−7). To our surprise, a
94% yield was obtained when PCy3 (tricyclohexylphosphine)
was used as ligand (entry 8). Subsequently, some other
oxidants and bases were also evaluated, but lower yields were
observed (entries 9−13). It is noteworthy that only 18% yield
was obtained in the absence of oxidant (entry 14). Polar
solvents such as DMF, DMSO and MeCN were unfavorable for
this transformation (entries 15−17). Lower yields were
observed when the reaction was conducted at 100 °C or
when the loading of catalyst reduced to 5 mol % (entries 18 and
19).
With these optimized conditions in hand, we surveyed the
substrate scope of N-aryltrifluoroacetimidoyl chlorides and
arylboronic acids (Table 2). Initially, a variety of arylboronic
acids were investigated by reacting with substrate 1a under
standard conditions. The results demonstrated that both
electron-rich and electron-poor phenylboronic acids were
suitable coupling partners, and the reactions afforded the
corresponding products in moderate to excellent yields (4−
14). o- or p-methyl-substituted phenylboronic acid gave the
product in 72% and 86% yield, respectively (4 and 5). Similar
results were obtained for MeO-substituted phenylboronic acid
(6 and 7). The reactions of biphenyl-4-boronic acid also
Phenanthridines are important heteroaromatic compounds and
commonly encountered in biologically active molecules,1
natural products,2 and optoelectronic materials.3 As a
consequence, a number of useful synthetic procedures have
been developed to prepare phenanthridines and their
derivatives.4 However, simple, mild, and versatile preparations
of phenanthridines with specific substitution patterns are still
highly desirable. For example, efficient synthetic methods for
trifluoromethylated phenanthridines are scarcely reported
although the incorporation of a CF3 group into aromatics
often enhances their biological activity and has become a
powerful and widely used strategy in the process of drug
design.5,6
Recently, transition-metal-catalyzed arene C−H bond
functionalization reactions have emerged as versatile tools for
the atom- and step-economical assembly of aromatic
compounds.7,8 For example, Yoshikai and co-workers reported
a cobalt-catalyzed ortho-arylation of aromatic imines with aryl
chlorides.8 As part of our ongoing studies toward the synthesis
of trifluoromethylated heterocyclic compounds,9 we have been
investigating the preparation of CF3-containing phenanthri-
dines from our previously reported building blocks which can
be conveniently prepared from 2-bromoaniline derivative and
trifluoroacetic acid.10 Herein, we report a simple and efficient
protocol for the synthesis of 6-trifluoromethylphenanthridines
by the palladium-catalyzed tandem Suzuki coupling reaction
and subsequent intramolecular C−H arylation of N-aryltri-
fluoroacetimidoyl chlorides with arylboronic acids in one pot
(Scheme 1).
Scheme 1
Received: April 7, 2013
© XXXX American Chemical Society
A
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a
Table 1. Screening Conditions
b
entry
[Pd]
base
ligand
oxidant
solvent
yield (%)
1
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
t-BuONa
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
PPh3
PPh3
PPh3
PPh3
XPhos
SPhos
RuPhos
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
49
53
5
2
3
4
73
47
51
45
94
59
31
68
88
5
5
6
7
8
9
10
11
12
13
14
15
16
17
AgOTf
K2S2O8
Ag2CO3
Ag2CO3
18
11
trace
NR
81
65
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
DMSO
CH3CN
toluene
toluene
c
18
d
19
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [Pd] (10 mol %), ligand (20 mol %), oxidant (2 equiv), and base (2 equiv) in solvent (2 mL)
b
c
d
at 120 °C under N2 atmosphere for 24 h. Isolated yield. At 100 °C. (PPh3)4 (5 mol %).
afforded the desired product in 81% yield (8). 4-Fluoro- and 4-
chlorophenylboronic acid provided 67% and 82% yields,
respectively (9 and 10). 2-Position C−H-arylated product
was exclusively obtained in 86% yield using 3-nitrophenylbor-
onic acid as substrate (11). Other cyclizations of phenylboronic
acids bearing strongly electron-withdrawing groups (such as
cyano, acetyl, and trifluoromethyl) proceeded smoothly to give
their corresponding products in 66−87% yields (12−14).
Interestingly, naphthalen-1-ylboronic acid underwent the
tandem reactions to afford β-position C−H arylation product
in a 51% yield (15). Subsequently, various substituents on the
3- or 4-position of N-(2-bromophenyl)trifluoroacetimidoyl
chlorides were tested. The reaction between 4-methyl-
substituted phenylimine and various arylboronic acids gave
excellent yields (16−18). 4-Chloro- and 4-fluorophenylimine
also provided the corresponding product in 72−93% yields
(19−21). The cyclization of 3-trifluoromethylphenylimine
proceeded smoothly to give the corresponding product in
82% yield (22), whereas 3-nitrophenylimine afforded a lower
yield (42%, 23).
3), which suggested that the directing group of imine probably
played a key role during C−H arylation reaction.
On the basis of the observed results and the reported
mechanism,11 a possible mechanism was proposed as outlined
in Scheme 3. The reaction afforded product 3 in poor yield in
the absence of oxidant, which suggested that the C−H arylation
possibly proceeded through a Pd(II)/Pd(IV) pathway although
a Pd(0)/Pd(II) pathway could not be ruled out. The Suzuki
coupling reaction between substrate 1a and 2a occurred
preferentially at low temperature to provide compound 24. In
path a, the oxidative addition of aryl bromide 24 to Pd(0)
species afforded intermediate A. The elimination of HBr might
yield palladacycle B, and the following reductive elimination
furnished product 3. In path b, imine-directing C−H activation
produced palladium(II) complex C. Intramolecular oxidative
addition with phenyl bromide moiety provided seven-
membered palladacycle D,12 and the subsequent reductive
elimination afforded the desired product 3 and regenerated
Pd(II) species. Study of the detailed mechanism is in progress.
To elucidate the mechanism of the transformation, some
control experiments were carried out as shown in Scheme 2.
First, treatment of substrate 1a with phenylboronic acid 2a in
the presence of Pd(PPh3)4, PCy3, Ag2CO3, and K2CO3 at 60 °C
for 5 h afforded the 2-bromo-N-(2,2,2-trifluoro-1-
phenylethylidene)aniline 24 in 90% yield, and no product 3
was detected (Scheme 2, eq 1). These results indicated that the
Suzuki coupling reaction occurred preferentially under the
standard conditions. As expected, compound 24 could be
converted into the desired product 3 in a 93% yield under
standard conditions for 12 h (eq 2). It is noteworthy that no
cyclization product was detected using o-bromostyrene
derivative 25 as substrate under the standard conditions (eq
CONCLUSION
■
In summary, we have developed an efficient method for the
synthesis of trifluoromethylated phenanthridines. In the
presence of Pd(PPh3)4, PCy3, Ag2CO3, and K2CO3, a variety
of N-aryltrifluoroacetimidoyl chlorides underwent the tandem
Suzuki/C−H arylation reactions with arylboronic acids to
afford the corresponding phenanthridines in moderate to
excellent yields. The present process could be used for the
synthesis of trifluoromethyl-containing building blocks from
simple starting materials, and it also provided a new optional
route for constructing phenanthridine rings.
B
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a
Table 2. Palladium-Catalyzed Tandem Suzuki/C−H Arylation Reactions
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(PPh3)4 (10 mol %), PCy3 (20 mol %), Ag2CO3 (2 equiv) and K2CO3 (2 equiv) in toluene
(2 mL) at 120 °C under N2 atmosphere for 24 h.
Scheme 2. Control Experiments
EXPERIMENTAL SECTION
■
General Information. Chemicals were either purchased or
purified by standard techniques. 1H NMR and 13C NMR spectra
were measured on a 500 MHz spectrometer (1H: 500 MHz, 13C: 125
MHz), using CDCl3 as the solvent with tetramethylsilane (TMS) as an
internal standard at room temperature. Chemical shifts are given in δ
relative to TMS, the coupling constants J are given in Hz. 19F NMR
spectra were recorded on a 500 MHz spectrometer (19F: 470 MHz)
and are reported relative to the CFCl3 as the internal standard. High-
resolution mass spectra were recorded on ESI-Q-TOF mass
spectrometry. All reactions under nitrogen atmosphere were
conducted using standard Schlenk techniques. Column chromatog-
raphy was performed using EM silica gel 60 (300−400 mesh).
Typical Experimental Procedure for Synthesis of 6-
(Trifluoromethyl)phenanthridine. A mixture of N-(2-bromophen-
yl)-2,2,2-trifluoroacetimidoyl chloride (57.2 mg, 0.2 mmol), Pd-
(PPh3)4 (23.1 mg, 10 mol %), PCy3 (11.2 mg, 20 mol %), Ag2CO3
(110.4 mg, 2 equiv), K2CO3 (55.2 mg, 2 equiv), and phenylboronic
acid (29.3 mg, 1.2 equiv) in toluene (2 mL) was evacuated and
backfilled with nitrogen (3 cycles) and then stirred at 120 °C until
complete consumption of starting material as detected by TLC or
C
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Scheme 3. Possible Mechanism
GC−MS analysis. After the reaction was finished, the mixture was
poured into ethyl acetate, evaporated under vacuum. The residue was
purified by flash column chromatography (hexane/ethyl acetate) to
afford the desired product 3.
1H), 7.80−7.72 (m, 2H), 7.34−7.32 (m, 1H), 4.05 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 161.7, 146.1 (q, JC−F = 32.6 Hz), 142.1, 136.4,
131.1, 129.4, 128.6, 127.8 (q, JC−F = 3.4 Hz), 124.8, 122.0, 122.0 (q,
JC−F = 275.5 Hz), 118.4, 116.6, 103.1, 55.6; 19F NMR (470 MHz,
CDCl3) δ −63.3 (s, 3F); IR (neat, cm−1) 1616, 1393, 1177, 1113, 971,
839, 735; LRMS (EI, 70 eV) m/z 277 (M+•, 100), 278 (17), 234 (38),
178 (12), 164 (9); HRMS (ESI) Calcd for C15H11F3NO+ ([M + H]+)
278.0787, found 278.0799.
9-Phenyl-6-(trifluoromethyl)phenanthridine (8): pale yellow solid
(52.3 mg, 81% yield); mp 85.9−87.8 °C ; 1H NMR (500 MHz,
CDCl3) δ 8.85 (s, 1H), 8.68−8.66 (m, 1H), 8.45−8.43 (m, 1H),
8.30−8.29 (m, 1H), 8.00−7.98 (m, 1H), 7.81−7.77 (m, 4H), 7.57−
7.54 (m, 2H), 7.49−7.46 (m, 1H) ; 13C NMR (125 MHz, CDCl3) δ
146.4 (q, JC−F = 33.0 Hz), 144.1, 142.1, 140.0, 134.4, 131.2, 129.4,
129.2, 129.1, 128.6, 127.7, 127.5, 126.4 (q, JC−F = 3.4 Hz), 125.2,
122.1, 122.0 (q, JC−F = 275.4 Hz), 120.8, 120.6; 19F NMR (470 MHz,
CDCl3) δ −63.4 (s, 3F); IR (neat, cm−1) 1616, 1252, 1117, 973, 832,
762, 610; LRMS (EI, 70 eV) m/z 323 (M+•, 100), 254 (36), 226 (12),
127 (11), 113 (14); HRMS (ESI) calcd for C20H13F3N+ ([M + H]+)
324.0995, found 324.1005.
9-Fluoro-6-(trifluoromethyl)phenanthridine (9): pale yellow solid
(35.5 mg, 67% yield); mp 52.4−54.3 °C; 1H NMR (500 MHz,
CDCl3) δ 8.50−8.48 (m, 1H), 8.43−8.40 (m, 1H), 8.31−8.28 (m,
2H), 7.87−7.79 (m, 2H), 7.53−7.49 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 164.1 (d, JC−F = 252.9 Hz), 146.0 (q, JC−F = 32.0 Hz), 142.0,
136.6 (d, JC−F = 9.5 Hz), 131.2, 130.1, 129.3, 129.1 (q, JC−F = 9.6 Hz),
124.6 (d, JC−F = 4.3 Hz), 122.3, 121.8 (q, JC−F = 275.3 Hz), 118.8,
117.5 (d, JC−F = 23.9 Hz), 107.8 (d, JC−F = 19.9 Hz); 19F NMR (470
MHz, CDCl3) δ −63.4 (s, 3F), −104.4 (s, 1F) IR (neat, cm−1) 1625,
1256, 1116, 972, 837, 705, 557; LRMS (EI, 70 eV) m/z 262 (M+•,
100), 196 (63), 170 (5) 169 (18), 133 (6); HRMS (ESI) calcd for
C14H8F4N+ ([M + H]+) 266.0588, found 266.0579.
6-(Trifluoromethyl)phenanthridine (3):5 pale yellow solid (46.4
1
mg, 94% yield); mp 71.2−73.1 °C; H NMR (500 MHz, CDCl3) δ
8.70 (d, J = 8.5 Hz, 1H), 8.62−8.60 (m, 1H), 8.39−8.37 (m, 1H),
8.30−8.28 (m, 1H), 7.94−7.91 (m, 1H), 7.83−7.76 (m, 3H); 13C
NMR (125 MHz, CDCl3) δ 146.5 (q, JC−F = 32.8 Hz), 141.7, 133.9,
131.4, 131.1, 129.3, 129.2, 128.0, 125.9 (q, JC−F = 3.3 Hz), 125.1,
122.5, 122.1, 121.9 (q, JC−F = 275.5 Hz), 121.7; 19F NMR (470 MHz,
CDCl3) δ −63.5 (s, 3F); IR (neat, cm−1): 1620, 1382, 1179, 972, 757,
611; LRMS (EI, 70 eV) m/z 247 (M+•, 100), 178 (60), 151 (30), 124
(9), 75 (8); HRMS (ESI) calcd for C14H9F3N+ ([M + H]+) 248.0682,
found 248.0680.
7-Methyl-6-(trifluoromethyl)phenanthridine (4): pale yellow solid
(37.6 mg, 72% yield); mp 46.8−48.5 °C; 1H NMR (500 MHz,
CDCl3) δ 8.56−8.51 (m, 2H), 8.22−8.20 (m, 1H), 7.78−7.70 (m,
3H), 7.56 (d, J = 7.0 Hz, 1H), 2.81 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 145.0 (q, JC−F = 33.5 Hz), 140.6, 135.8, 135.5, 132.6, 130.6,
130.4, 129.2, 129.1, 125.3, 122.3, 122.2, 122.0 (q, JC−F = 273.8 Hz),
120.7, 23.4; 19F NMR (470 MHz, CDCl3) δ −59.7 (s, 3F); IR (neat,
cm−1) 1600, 1346, 1168, 1121, 963, 758, 716; LRMS (EI, 70 eV) m/z
261 (M+•, 100), 241 (15), 192 (41), 165 (43), 82 (11); HRMS (ESI)
calcd for C15H11F3N+ ([M + H]+) 262.0838, found 262.0840.
9-Methyl-6-(trifluoromethyl)phenanthridine (5): pale yellow solid
(44.9 mg, 86% yield); mp 51.4−53.2 °C; 1H NMR (500 MHz,
CDCl3) δ 8.55 (d, J = 7.5 Hz, 1H), 8.42 (s, 1H), 8.26−8.23 (m, 2H),
7.79−7.73 (m, 2H), 7.55 (d, J = 8.5 Hz, 1H), 2.64 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 146.4 (q, JC−F = 32.8 Hz), 142.0, 141.9, 134.1,
131.0, 129.8, 129.1, 128.9, 125.7 (q, JC−F = 3.3 Hz), 124.9, 122.1,
122.0, 121.9 (q, JC−F = 275.5 Hz), 119.8, 22.3; 19F NMR (470 MHz,
CDCl3) δ −63.5 (s, 3F); IR (neat, cm−1) 1626, 1251, 970, 744, 623,
9-Chloro-6-(trifluoromethyl)phenanthridine (10): pale yellow
556; LRMS (EI, 70 eV) m/z 261 (M+•, 100), 241 (15), 165 (43), 192
solid (46.1 mg, 82% yield); mp 94.5−96.3 °C; H NMR (500 MHz,
1
+
(41), 82 (11); HRMS (ESI) calcd for C15H11F3N+ ([M + H
262.0838, found 262.0847.
)
CDCl3) δ 8.64 (s, 1H), 8.52−8.50 (m, 1H), 8.32−8.28 (m, 2H),
7.86−7.79 (m, 2H), 7.72−7.70 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 146.1 (q, JC−F = 33.3 Hz), 142.1, 138.1, 135.3, 131.2, 130.0,
129.5, 128.8, 128.2, 127.5 (q, JC−F = 3.3 Hz), 122.3, 122.1, 121.7 (q,
JC−F = 275.4 Hz), 120.0; 19F NMR (470 MHz, CDCl3) δ −63.5 (s,
3F); IR (neat, cm−1) 1607, 1383, 1249, 1113, 971, 825, 767; LRMS
(EI, 70 eV) m/z 281 (M+•, 100, 35Cl), 283 (33, 37Cl), 177 (63), 212
(43), 150 (16), 75 (12); HRMS (ESI) calcd for C14H8F3NCl+ ([M +
H]+) 282.0292, found 282.0296.
7-Methoxy-6-(trifluoromethyl)phenanthridine (6): pale yellow
1
solid (31.6 mg, 57% yield); mp 92.1−94.0 °C; H NMR (500 MHz,
CDCl3) δ 8.54−8.52 (m, 1H), 8.24 (d, J = 8.0 Hz, 2H), 7.82−7.72 (m,
3H), 7.15 (d, J = 8.0 Hz, 1H), 4.05 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 156.8, 144.6 (q, JC−F = 34.8 Hz), 141.5, 136.2, 132.0, 130.9,
129.3, 129.0, 124.6, 122.4, 122.0 (q, JC−F = 273.4 Hz), 114.5, 114.3,
109.2, 56.1; 19F NMR (470 MHz, CDCl3) δ −63.7 (s, 3F); IR (neat,
cm−1) 1609, 1462, 1275, 1142, 963, 739, 682; LRMS (EI, 70 eV) m/z
277 (M+•, 100), 234 (53), 208 (14), 178 (12), 164 (10), 135 (8);
HRMS (ESI) calcd for C15H11F3NO+ ([M + H]+) 278.0787, found
278.0789.
10-Nitro-6-(trifluoromethyl)phenanthridine (11): pale yellow solid
1
(50.2 mg, 86% yield); mp 129.7−131.5 °C; H NMR (500 MHz,
CDCl3) δ 8.58−8.56 (m, 1H), 8.35−8.33 (m, 1H), 8.12−8.10 (m,
1H), 8.04−8.03 (m, 1H), 7.91−7.85 (m, 2H), 7.77−7.73 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 148.2, 145.6 (q, JC−F = 33.4 Hz), 142.7,
131.8, 130.9, 130.0, 129.2 (q, JC−F = 3.6 Hz), 127.5, 126.5, 125.1,
124.0, 123.1, 121.5 (q, JC−F = 275.5 Hz), 120.5; 19F NMR (470 MHz,
9-Methoxy-6-(trifluoromethyl)phenanthridine (7): pale yellow
solid (40.4 mg, 73% yield); mp 150.4−152.3 °C; 1H NMR (500
MHz, CDCl3) δ 8.49 (d, J = 8.0 Hz, 1H), 8.29−8.23 (m, 2H), 7.94 (s,
D
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CDCl3) δ −63.1 (s, 3F); IR (neat, cm−1) 1521, 1172, 1028, 823, 764,
657; LRMS (EI, 70 eV) m/z 262 (M+•, 100), 260 (80), 242 (77), 191
(32), 292 (31), 234 (25), 139 (23); HRMS (ESI) calcd for
1621, 1256, 1105, 812, 710, 535; LRMS (EI, 70 eV) m/z 275 (M+•,
100), 255 (35), 240 (12), 206 (14), 190 (17), 102 (9); HRMS (ESI)
calcd for C16H13F3N+ ([M + H]+) 276.0995, found 276.0997.
9-Chloro-2-methyl-6-(trifluoromethyl)phenanthridine (18): pale
+
C14H8F3N2O2 ([M + H]+) 293.0533, found 293.0538.
1
6-(Trifluoromethyl)phenanthridine-9-carbonitrile (12): pale yel-
yellow solid (50.2 mg, 85% yield); mp 96.5−98.1 °C; H NMR (500
1
low solid (38.6 mg, 71% yield); mp 192.4−194.2 °C; H NMR (500
MHz, CDCl3) δ 8.56 (s, 1H), 8.26−8.24 (m, 1H), 8.22 (s, 1H), 8.13
(d, J = 8.0 Hz, 1H), 7.67−7.62 (m, 2H), 2.64 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 145.1 (q, JC−F = 33.0 Hz), 140.4, 139.9, 137.8, 134.9,
131.8, 130.9, 128.5, 127.4 (q, JC−F = 3.3 Hz), 123.8, 122.2, 121.8 (q,
JC−F = 275.1 Hz), 121.6, 120.0, 22.1; 19F NMR (470 MHz, CDCl3) δ
−63.4 (s, 3F); IR (neat, cm−1) 1607, 1383, 1114, 971, 814, 708; LRMS
(EI, 70 eV) m/z 295 (M+•, 100, 35Cl), 297 (34, 37Cl), 275 (42), 190
(40), 163 (20), 82 (20); HRMS (ESI) calcd for C15H10F3NCl+ ([M +
H]+) 296.0449, found 296.0455.
MHz, CDCl3) δ 9.03 (s, 1H), 8.59−8.57 (m, 1H), 8.48−8.46 (m, 1H),
8.35−8.33 (m, 1H), 7.97−7.95 (m, 1H), 7.92−7.88 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 145.9 (q, JC−F = 33.6 Hz), 142.1, 133.7,
131.5, 130.7, 130.4, 129.3, 127.9, 127.1 (q, JC−F = 3.4 Hz), 123.7,
123.1, 122.0, 121.5 (q, JC−F = 275.4 Hz), 117.9, 115.0; 19F NMR (470
MHz, CDCl3) δ −63.5 (s, 3F); IR (neat, cm−1) 1374, 1174, 972, 772,
569, 549; LRMS (EI, 70 eV) m/z 272 (M+•, 100), 203 (52), 176 (26),
+
149 (7), 136 (5); HRMS (ESI) calcd for C15H8F3N2 ([M + H]+)
2-Chloro-6-(trifluoromethyl)phenanthridine (19): pale yellow
solid (49.5 mg, 88% yield); mp 101.3−103.1 °C; 1H NMR (500
MHz, CDCl3) δ 8.53 (d, J = 8.5 Hz, 1H), 8.47 (s, 1H), 8.3 (d, J = 8.5
Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.91−7.88 (m, 1H), 7.79−7.76 (m,
1H), 7.72−7.70 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 146.7 (q,
JC−F = 33.1 Hz), 140.1, 135.4, 132.8, 132.5, 131.6, 129.9, 128.7, 126.1,
126.0 (q, JC−F = 3.3 Hz), 122.5, 121.9, 121.8 (q, JC−F = 275.5 Hz),
121.7; 19F NMR (470 MHz, CDCl3) δ −63.5 (s, 3F); IR (neat, cm−1)
1601, 1387, 1178, 973, 829, 767,681; LRMS (EI, 70 eV) m/z 281
(M+•, 100, 35Cl), 283 (33, 37Cl), 212 (41), 177 (73), 150 (14), 123
(7); HRMS (ESI) Calcd for C14H8F3NCl+ ([M + H]+) 282.0292,
found 282.0299.
273.0634, found 273.0634.
1-(6-(Trifluoromethyl)phenanthridin-9-yl)ethanone (13): pale
yellow solid (38.1 mg, 66% yield); mp 154.0−156.0 °C; H NMR
(500 MHz, CDCl3) δ 9.26 (s, 1H), 8.70−8.68 (m, 1H), 8.45 (d, J =
8.5 Hz, 1H), 8.32−8.30 (m, 1H), 8.26 (d, J = 8.5 Hz, 1H), 7.87−7.85
(m, 2H), 2.83 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 197.3, 146.1
(q, JC−F = 33.3 Hz), 142.0, 138.3, 133.8, 131.4, 130.0, 129.9, 126.7,
1
126.5 (q, JC−F = 3.4 Hz), 125.2, 123.7, 123.0, 122.1, 121.7 (q, JC−F
=
275.4 Hz), 27.0; 19F NMR (470 MHz, CDCl3) δ −63.6 (s, 3F); IR
(neat, cm−1) 1686, 1244, 1117, 972, 768, 548; LRMS (EI, 70 eV) m/z
274 (M+•, 100), 289 (62), 246 (45), 226 (27), 151 (13), 247 (8);
HRMS (ESI) calcd for C16H11F3NO+ ([M + H]+) 290.0787, found
290.0793.
2-Chloro-6-(trifluoromethyl)phenanthridine-9-carbonitrile (20):
pale yellow solid (44.1 mg, 72% yield); mp 177.5−179.4 °C; 1H
NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 8.56 (s, 1H), 8.51−8.49 (m,
1H), 8.28 (d, J = 8.5 Hz, 1H), 8.02−8.00 (m, 1H), 7.88−7.85 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 146.1 (q, JC−F = 33.9 Hz), 140.6,
136.9, 132.9, 132.8, 131.4, 130.1, 127.8, 127.3 (q, JC−F = 3.4 Hz),
124.8, 123.3, 121.8, 121.4 (q, JC−F = 275.6 Hz), 117.6, 115.4; 19F NMR
(470 MHz, CDCl3) δ −63.5 (s, 3F); IR (neat, cm−1) 1507, 1254,
1133, 975, 826, 743, 680; LRMS (EI, 70 eV) m/z 306 (M+•, 100,
35Cl), 308 (34, 37Cl), 237 (36), 202 (52), 175 (15), 153 (6); HRMS
(ESI) calcd for C15H7F3N2Cl+ ([M + H] +) 307.0245, found 307.0247.
2-Fluoro-6-(trifluoromethyl)phenanthridine (21): pale yellow solid
6, 9-Bis(trifluoromethyl)phenanthridine (14): pale yellow solid
(54.8 mg, 87% yield); mp 87.2−89.1 °C; 1H NMR (500 MHz,
CDCl3) δ 8.96 (s, 1H), 8.64−8.62 (m, 1H), 8.51 (d, J = 9.0 Hz, 1H),
8.34−8.32 (m, 1H), 7.98−7.96 (m, 1H), 7.90−7.85 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 145.8 (q, JC−F = 27.3 Hz), 142.1, 133.8,
132.9 (q, JC−F = 32.8 Hz), 131.5, 130.3, 130.0, 127.1 (q, JC−F = 3.4
Hz), 124.6, 124.1 (q, JC−F = 2.9 Hz), 123.6 (q, JC−F = 271.3 Hz), 123.2,
122.1, 121.6 (q, JC−F = 275.4 Hz), 120.1 (q, JC−F = 4.4 Hz); 19F NMR
(470 MHz, CDCl3) δ −63.5 (s, 3F), −62.9 (s, 3F); IR (neat, cm−1)
1576, 1321, 1077, 974, 829, 740, 684; LRMS (EI, 70 eV) m/z 315
(M+•, 100), 296 (9), 246 (58), 226 (29), 177 (15); HRMS (ESI) calcd
for C15H8F6N+ ([M + H]+) 316.0556, found 316.0561.
5-(Trifluoromethyl)benzo[i]phenanthridine (15): pale yellow solid
(30.3 mg, 51% yield); mp 138.7−140.5 °C; H NMR (500 MHz,
CDCl3) δ 8.74 (d, J = 8.5 Hz, 1H), 8.53−8.47 (m, 2H), 8.25−8.23 (m,
1H), 8.08 (d, J = 9.0 Hz, 1H), 7.91−7.89 (m, 1H), 7.77−7.69 (m,
2H), 7.66−7.59 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 144.4 (q,
JC−F = 33.4 Hz), 142.4, 135.1, 133.1, 132.9, 130.4, 129.6, 129.0, 128.4,
1
(49.3 mg, 93% yield); mp 104.3−106.2 °C; H NMR (500 MHz,
CDCl3) δ 8.51 (d, J = 8.5 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.27−8.24
(m, 1H), 8.15−8.13 (m, 1H), 7.92−7.89 (m, 1H), 7.80−7.77 (m, 1H),
1
7.54−7.50 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 162.6 (d, JC−F
=
249.1 Hz), 145.8 (q, JC−F = 32.9 Hz), 138.5, 133.5 (d, JC−F = 9.5 Hz),
133.3, 131.4, 128.7, 126.7, 126.0, 122.7, 121.9 (q, JC−F = 275.3 Hz),
121.8, 118.4 (d, JC−F = 24.4 Hz), 107.1 (d, JC−F = 23.5 Hz); 19F NMR
(470 MHz, CDCl3) δ −63.5 (s, 3F), −108.8 (s, 1F); IR (neat, cm−1)
1619, 1453, 1128, 971, 863, 767, 557; LRMS (EI, 70 eV) m/z 265
(M+•, 100), 215 (5), 196 (71), 169 (21), 132 (7); HRMS (ESI) calcd
for C14H8F4N+ ([M + H]+) 266.0588, found 266.0582.
128.3, 127.7 (q, JC−F = 7.9 Hz), 127.4, 127.2, 124.8, 122.6 (q, JC−F
=
274.6 Hz), 122.6, 119.9, 119.6; 19F NMR (470 MHz, CDCl3) δ −60.1
(s, 3F); IR (neat, cm−1) 1322, 1125, 945, 736, 594, 535; LRMS (EI, 70
eV) m/z 297 (M+•, 100), 228 (78), 200 (22), 138 (14), 100 (30);
HRMS (ESI) calcd for C18H11F3N+ ([M + H]+) 298.0838, found
298.0842.
3, 6-Bis(trifluoromethyl)phenanthridine (22): pale yellow solid
1
(51.7 mg, 82% yield), mp 104.7−106.5 °C; H NMR (500 MHz,
2-Methyl-6-(trifluoromethyl)phenanthridine (16): pale yellow
solid (48.5 mg, 93% yield); mp 100.7−102.5 °C; 1H NMR (500
MHz, CDCl3) δ 8.66 (d, J = 8.5 Hz, 1H), 8.36−8.34 (m, 2H), 8.16 (d,
J = 8.0 Hz, 1H), 7.90−7.87 (m, 1H), 7.75−7.72 (m, 1H), 7.63−7.61
(m, 1H), 2.65 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 145.5 (q, JC−F
= 32.6 Hz), 140.1, 139.5, 133.6, 131.1 (2C), 130.8, 127.9, 125.8 (q,
JC−F = 3.3 Hz), 125.0, 122.5, 122.0 (q, JC−F = 275.3 Hz), 121.8, 121.6,
22.1; 19F NMR (470 MHz, CDCl3) δ −63.3 (s, 3F); IR (neat, cm−1)
1613, 1257, 1109, 971, 825, 768; LRMS (EI, 70 eV) m/z 261 (M+•,
100), 241 (35), 190 (18), 165 (16), 121 (7), 82 (7); HRMS (ESI)
calcd for C15H11F3N+ ([M + H]+) 262.0838, found 262.0842.
2,9-Dimethyl-6-(trifluoromethyl)phenanthridine (17): pale yellow
CDCl3) δ 8.68−8.65 (m, 2H), 8.56 (s, 1H), 8.40 (d, J = 8.5 Hz, 1H),
7.99−7.94 (m, 2H), 7.86−7.83 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 148.0 (q, JC−F = 33.1 Hz), 141.0, 133.2, 132.0, 131.2 (q, JC−F
= 33.0 Hz), 129.3, 128.6 (q, JC−F = 4.1 Hz), 127.3, 126.2 (q, JC−F = 3.3
Hz), 125.0 (q, JC−F = 3.4 Hz), 123.7 (q, JC−F =270.9 Hz), 123.2, 122.9,
122.3, 121.6 (q, JC−F = 275.8 Hz); 19F NMR (470 MHz, CDCl3) δ
−63.7 (s, 3F), −62.5 (s, 3F); IR (neat, cm−1) 1610, 1332, 1116, 971,
834, 775, 686; LRMS (EI, 70 eV) m/z 315 (M+•, 100), 296 (10), 246
(66), 226 (38), 177 (22); HRMS (ESI) calcd for C15H8F6N+ ([M +
+
H] ) 316.0556, found 316.0559.
3-Nitro-6-(trifluoromethyl)phenanthridine (23): pale yellow solid
1
(24.5 mg, 42% yield); mp 168.7−170.2 °C; H NMR (500 MHz,
1
solid (49.5 mg, 90% yield); mp 99.3−101.2 °C; H NMR (500 MHz,
CDCl3) δ 9.15 (s, 1H), 8.77−8.74 (m, 2H), 8.58−8.56 (m, 1H), 8.46
(d, J = 8.5 Hz, 1H), 8.08−8.05 (m, 1H), 7.95−7.92 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 149.0 (q, JC−F = 33.5 Hz), 147.8, 141.2,
132.9, 132.4, 130.1, 129.5, 126.8, 126.4 (q, JC−F = 3.4 Hz), 123.7,
123.4, 122.8, 122.7, 121.4 (q, JC−F = 275.9 Hz); 19F NMR (470 MHz,
CDCl3) δ −63.8 (s, 3F); IR (neat, cm−1) 1610, 1539, 1345, 1121, 974,
734; LRMS (EI, 70 eV) m/z 292 (M+•, 100), 262 (73), 234 (44), 226
CDCl3) δ 8.40 (s, 1H), 8.32 (s, 1H), 8.23−8.21 (m, 1H), 8.13 (d, J =
8.5 Hz, 1H), 7.60−7.58 (m, 1H), 7.54−7.52 (m, 1H), 2.64 (s, 3H),
2.63 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 145.4 (q, JC−F = 32.6
Hz), 141.7, 140.2, 139.2, 133.8, 130.9, 130.7, 129.6, 125.6 (q, JC−F
=
3.3 Hz), 124.8, 122.1 (q, JC−F = 275.4 Hz), 122.0, 121.6, 119.9, 22.3,
22.1; 19F NMR (470 MHz, CDCl3) δ −63.4 (s, 3F); IR (neat, cm−1)
E
dx.doi.org/10.1021/jo4007255 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(54), 177 (20), 149 (12); HRMS (ESI) calcd for C14H8F3N2O2+ ([M
+ H]+) 293.0533, found 293.0536.
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Hagmann, W. K. J.
Med. Chem. 2008, 51, 4359.
2-Bromo-N-(2,2,2-trifluoro-1-phenylethylidene)aniline (24): pale
yellow liquid (58.9 mg, 90% yield); H NMR (500 MHz, CDCl3) δ
(7) Recent reviews: (a) Daugulis, O. Top. Curr. Chem. 2010, 292, 57.
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Synthesis 2012, 966.
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1
7.53−7.51 (m, 1H), 7.37−7.32 (m, 1H), 7.31−7.25 (m, 4H), 7.08−
7.05 (m, 1H), 6.91−6.88 (m, 1H), 6.50−6.48 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 158.6 (q, JC−F = 34.0 Hz), 146.5, 133.7 (q, JC−F
= 19.4 Hz), 132.8, 130.7, 128.5, 128.1, 127.8, 126.1, 119.9, 119.6 (q,
JC−F = 277.8 Hz), 114.3; 19F NMR (470 MHz, CDCl3) δ −69.8 (s,
3F); IR (neat, cm−1) 1673, 1466, 1231, 1134, 970, 760, 697; LRMS
(EI, 70 eV) m/z 258 (100), 260 (91), 327 (M+•, 32, 79Br), 329 (32,
81Br), 76 (24), 155 (20); HRMS (ESI) calcd for C14H10BrF3N+ ([M +
+
H] ) 327.9949, found 327.9943.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 3−24. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zxg@wzu.edu.cn.
■
Notes
The authors declare no competing financial interest.
(12) (a) Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106,
5759. (b) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44,
4046. (c) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res.
2009, 42, 1074.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21002070 and 21272177) and Zhejiang Provincial Natural
Science Foundation of China (No. Y4100307) for financial
support.
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dx.doi.org/10.1021/jo4007255 | J. Org. Chem. XXXX, XXX, XXX−XXX