Synthesis of Phenanthridinones by Palladium-Catalyzed Cyclization of N -Aryl-2-aminopyridines with 2-Iodobenzoic Acids in Water

Article abstract of DOI:10.1055/s-0039-1691538

The first Pd-catalyzed cyclization of N -aryl-2-aminopyridines with 2-iodobenzoic acids for the synthesis of phenanthridinones through C-H bond activation under very low catalyst loadings (down to 0.1 molpercent Pd) in water is reported. This protocol features a broad substrate scope and provides easy efficient access to various phenanthridinones.

Full text of DOI:10.1055/s-0039-1691538

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
X. Ding et al.
Letter
Synlett
Synthesis of Phenanthridinones by Palladium-Catalyzed Cycli-
zation of N-Aryl-2-aminopyridines with 2-Iodobenzoic Acids in
Water
Xiaojuan Dinga
Lei Zhanga
Yiyang Maoa
Binsen Ronga
Ning Zhua
Jindian Duan*a
Het
N
N
H
N
N
I
H2O
O
Ar1
Ar2
Het
+
Ar1
Pd(OAc)2/Ag2O
120 °C, 3 h
CO2H
Ar2
low catalyst loading (down to 0.1 mol% Pd)
water as the solvent
Kai Guo*a,b
0
0
0
0-0
0
0
2-0
0
1
3-
3
2
6
3
28 examples
up to 93% yield
good functional group tolerance
a College of Biotechnology and Pharmaceutical Engineering,
Nanjing Tech University, 30 Puzhu Rd S., Nanjing 211816,
P. R. of China
duanjd@njtech.edu.cn
guok@njtech.edu.cn
b State Key Laboratory of Materials-Oriented Chemical
Engineering, Nanjing Tech University, 30 Puzhu Rd S.,
Nanjing 211816, P. R. of China
Received: 13.10.2019
Accepted after revision: 03.12.2019
Published online: 16.12.2019
aryl halides,10 benzynes,11 aniline,12 aryl(triethoxy)sila-
nes,13 boronic acids,14 or others15 (Figure 1). Among these,
the palladium-catalyzed direct functionalization of C–H
bonds is an important synthetic tool for the synthesis of
phenanthridinones. However, these routes suffer from such
disadvantages as long reaction times, the need for inert at-
mospheric conditions, the necessity for large amounts of
catalysts or complex ligands, and the use of toxic or volatile
organic solvents. Although preparations of phenanthridi-
nones at low catalyst loadings (1 mol% or 0.1 mol%) have
been documented, the palladium pincer-type complexes
used often required preparations involving multistep syn-
thetic sequences.4h,14b Therefore, the development of an en-
vironmentally benign and cost-effective synthetic proce-
dure is highly desirable from the viewpoint of green chem-
istry. Here, we report the first synthesis of
phenanthridinones based on pyridinyl group-assisted pal-
ladium-catalyzed cyclization of N-aryl-2-aminopyridines
with 2-iodobenzoic acids at very low catalyst loadings
(down to 0.1 mol% Pd) in water.
To commence our studies, we selected N-phenyl-2-ami-
nopyridine (1a) and 2-iodobenzoic acid (2a) as model sub-
strates to optimize the reaction conditions. The reaction of
1a and 2a was first investigated in the presence of 0.1 mol%
Pd(OAc)2 as the catalyst and Ag2CO3 as an additive in water
at 120 °C for three hours under an air atmosphere. Gratify-
ingly, the desired phenanthridinone 3a was isolated in 85%
yield (Table 1, entry 1). However, a sharp decrease in yield
was observed in the absence of the additive (entry 2). On
the basis of these encouraging results, several additives
were evaluated, and Ag2O was found to be the most suitable
DOI: 10.1055/s-0039-1691538; Art ID: st-2019-l0548-l
Abstract The first Pd-catalyzed cyclization of N-aryl-2-aminopyridines
with 2-iodobenzoic acids for the synthesis of phenanthridinones
through C–H bond activation under very low catalyst loadings (down to
0.1 mol% Pd) in water is reported. This protocol features a broad sub-
strate scope and provides easy efficient access to various phenanthridi-
nones.
Key words phenanthridinones, palladium catalysis, cyclization, aryl-
aminopyridines, iodobenzoic acids
Phenanthridinones, which consist of three fused six-
membered rings, are frequently found in complex natural
alkaloids and pharmaceutically active compounds exhibit-
ing a broad range of biological activities, including antitu-
mor, antivirus, anti-HIV, and DNA-topoisomerase-inhibito-
ry activities.1 In recent decades, considerable efforts have
been directed towards the synthesis of various phenan-
thridinones.2 Most of these approaches have focused on: (1)
amide bond formation in 2′-aminobiphenyl-2-carboxylic
esters or 2′-halobiphenyl-2-carbonitriles;3 (2) intramolecu-
lar C–C bond formation through annulation of N-(2-
haloaryl)benzamides or C–H bond functionalization of N-
arylbenzamides;4 (3) aminocarbonylative cyclization of o-
arylanilines with CO, CO2, or other carbonyl sources;5 (4) in-
tramolecular C–H or C–halogen bond amidation of biaryl-
carboxyamides;6 (5) radical-based decarboxylative cycliza-
tion7 and coupling reactions of aryl carbamic chlorides with
aryl iodides;8 (6) transition-metal-catalyzed coupling of N-
substituted benzamides with aryl partners such as arenes,9
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
X. Ding et al.
Letter
Synlett
Table 1 Optimization of the Reaction Conditionsa
O
R
Ar2
Z
N
X
X
Ar1
Ar2
Ar1
Y
N
Y = NO2, RNH, Z = CO2R
Ar1
X = H, halogen
ref 4
H
catalyst (0.1 mol%)
additive (0.7 equiv)
Y = F or Br, Z = CN
I
N
N
O
N
Ar2
+
ref 3
NHR
O
O
solvent, 120 °C, 3 h
CO2H
1a
R
2a
3a
ref 5
ref 6
N
H
Ar2
Ar1
ref 9–15
NHR
X
Ar2
Ar2
X = H, halogen
R
N
Entry
Catalyst
Additive
Solvent
Yieldb (%)
Ar1
R
O
X
N
Cl
ref 8
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Ag2CO3
–
H2O
85
X = H, halogen
Ar1
ref 7
CO2H
+
O
This work
N
H2O
42
H
I
I
O
N
Ar2
Ar1
3
AgOAc
Ag2O
AgO
H2O
64
+
Ar2
Het
NH
CO2H
Ar1
4
H2O
H2O
93
low catalyst loading (down to 0.1 mol% Pd)
water as the solvent
broad substrate scope
Ar2
5
68
6
Cu(OAc)2
NH4OAc
CsOAc
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
H2O
55
Figure 1 Selected synthetic routes to phenanthridinones
7
H2O
48
8
H2O
trace
88
for the transformation, giving the desired product 3a in 93%
yield (entry 4). No further improvement of the yield was
obtained on screening of other Pd(II) species (entries 9–11).
A brief survey of solvents revealed that water was the opti-
mal solvent, and the use of MeCN decreased the yield to
41% (entry 12). Other organic solvents EtOAc, THF, or tolu-
ene were found to be inferior and suppressed the reaction
completely (entries 13–15). Finally, attempts to reduce the
reaction temperature failed, resulting in a lower yield of 3a
(entries 16 and 17). To demonstrate the possibility of large-
scale operation, a scaled-up experiment at the 10 mmol
scale was conducted and gave 3a in 85% yield (entry 18).
With the optimum reaction conditions in hand, we ex-
amined the scope and generality of the palladium-cata-
lyzed cyclization of N-aryl-2-aminopyridines 1 with 2-io-
dobenzoic acid 2a (Scheme 1).16 A variety of N-aryl-2-ami-
nopyridines bearing electron-donating (OMe, OPh) or
electron-withdrawing substituents (F, Cl, Br, CF3, CN) in the
para-, meta-, or ortho-positions of the phenyl ring were
well tolerated and were converted into the corresponding
products 3a–i in moderate to good yields. Note that elec-
tron-rich substrates tended to give relatively higher yields
than did their electron-deficient counterparts. Moreover,
disubstituted N-aryl-2-aminopyridines 1 were also suitable
substrates, affording the desired products 3j–m in yields of
65–70%. In addition, a 1-naphthalene-derived precursor
was successfully transformed into the product 3n in 78%
yield. We then examined the effects of substituents on the
pyridyl ring of the N-aryl-2-aminopyridines 1 and we found
that substrates with Me or CF3 groups on the C3 or C5 posi-
tion of the pyridine moiety reacted smoothly to furnish the
desired phenanthridinone products 3o–q in yields of 55–
63%. Notably, N-phenylquinolin-2-amine and N-phenyliso-
quinolin-1-amine were also compatible with the reaction
conditions, giving products 3r and 3s, albeit in low yields.
9
H2O
10
11
12
13
14
15
16c
17d
18e
PdBr2
H2O
84
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
H2O
82
MeCN
EtOAc
THF
41
trace
trace
trace
90
toluene
H2O
H2O
86
H2O
85
a Unless otherwise mentioned, all reactions were carried out by using 1a
(0.20 mmol), 2a (0.26 mmol), catalyst (0.1 mol%), additive (0.7 equiv), and
solvent (1.0 mL) under air at 120 °C for 3 h.
b Isolated yield.
c At 110 °C.
d At 100 °C.
e 10 mmol scale.
We then tested the palladium-catalyzed cyclization pro-
tocol with a set of 2-iodobenzoic acids 2 (Scheme 2). Re-
gardless of their electronic properties, steric hindrances,
and substitution positions on the aromatic ring, the various
2-iodobenzoic acids 2 reacted smoothly to afford the corre-
sponding phenanthridinones in medium to high yields. It is
particularly noteworthy that sterically congested 2-iodo-3-
methylbenzoic acid was an effective coupling partner, giv-
ing product 3u in 55% yield.
To further explore this reaction, we subjected N-(2-py-
rimidyl)anilines and 2-iodobenzoic acid (2a) to the reaction
conditions. However, the yields of the corresponding prod-
ucts 4a and 4b were markedly reduced, even with 10 mol%
Pd catalyst loadings, possibly as a result of the poor coordi-
nating ability of the pyrimidyl group. Moreover, simple di-
phenylamine (5) failed to deliver the desired product, high-
lighting the relevance of chelation assistance (Scheme 3).
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

C
X. Ding et al.
Letter
Synlett
Het
N
N
N
N
H
N
H
N
Pd(OAc)2 (0.1 mol%)
Ag2O (0.7 equiv)
Pd(OAc)2 (10 mol%)
Ag2O (0.7 equiv)
I
N
R
N
I
O
O
R
N
Ar
Het
+
Ar
+
+
N
H2O, 120 °C, 3 h
H2O, 120 °C, 3 h
CO2H
CO2H
1
2a
4
1
2a
3
R = H, 4a, 35%
R = Br, 4b, 24%
H
N
Pd(OAc)2 (10 mol%)
Ag2O (0.7 equiv)
I
N
N
N
N
O
N
N.R.
R
H2O, 120 °C, 3 h
O
O
CO2H
Me
N
R
N
O
N
5
2a
R
Scheme 3 Cyclization of N-(2-pyrimidyl)anilines or diphenylamine with
2-iodobenzoic acid (2a)
Me
R = H, 3a 93%
R = OMe, 3b 78%
R = OPh, 3c 65%
R = Br, 3d 75%
R = OMe, 3e 83%
R = CF3, 3f 58%
R = F, 3g 65%
3j 65%
R = Cl, 3h 72%
R = CN, 3i 61%
an acceptable overall yield. (Scheme 4a). Some control ex-
periments were also carried out to investigate the reaction
mechanism. The attempted reaction of N-phenyl-2-amino-
pyridine (1a) with methyl 2-iodobenzoate and iodobenzene
failed to give the desired products (Schemes 4b and 4c),
suggesting that the carboxyl group plays a crucial role in
this transformation. A subsequent reaction of the inde-
pendently synthesized substrate 7 under the standard reac-
tion conditions gave no product 3a (Scheme 4d), showing
that no acylation of N-phenyl-2-aminopyridine (1a) by 2-
iodobenzoic acid (2a) occurs in our transformation. Howev-
er, treatment of the palladacycle dimer I17 with 2a in water
at 120 °C for three hours resulted in the formation of the
product 3a in 91% yield (Scheme 4e).
N
N
N
N
OMe
Cl
Br
O
O
N
Cl
N
O
N
O
N
MeO
Me
3m 68%
3n 78%
3l 65%
3k 70%
CF3
N
Me
N
N
N
N
O
N
O
N
R
O
O
N
R = 3-Cl, 3o 62%
R = 2-Cl, 3p 55%
3q 63%
3r 56%
3s 57%
Scheme 1 Cyclization of N-aryl-2-aminopyridines 1 with 2-iodobenzo-
ic acid (2a). Reagents and conditions: 1 (0.20 mmol), 2a (0.26 mmol),
Pd(OAc)2 (0.1 mol%), Ag2O (0.7 equiv), H2O (1.0 mL), 3 h. The isolated
yields are reported.
N
H
O
N
Het
N
1) MeOTf, CH2Cl2
O
N
(a)
H
2) NaBH4, MeOH, rt
Pd(OAc)2 (0.1 mol%)
Ag2O (0.7 equiv)
I
N
N
O
N
Ar2
Ar1
Het
Ar1
+
6
3a
H2O, 120 °C, 3 h
CO2H
Ar2
1
2
3
67% in 2 steps
H
N
I
N
Pd(OAc)2 (0.1 mol%)
Ag2O (0.7 equiv)
N
N
N
N
+
3a
(b)
additive (1 equiv)
H2O, 120 °C, 3 h
No additive N.R.
PivOH, N.R.
CsOPiv, N.R
CO2Me
1a
O
O
O
O
N
N
N
N
Me
3u 55%
Br
Me
H
H
N
N
I
N
N
Pd(OAc)2 (0.1 mol%)
Ag2O (0.7 equiv)
3t 72%
3w 64%
3v 71%
Cl
N
+
(c)
(d)
additive (1 equiv)
H2O, 120 °C, 3 h
1a
N
N
N
N
O
O
Me
O
N
No additive N.R.
PivOH, N.R.
CsOPiv, N.R
N
F
F
Pd(OAc)2 (0.1 mol%)
Ag2O (0.7 equiv)
O
N
Me
N.R.
Me
H2O, 120 °C, 3 h
3y 65%
3x 60%
3z 56%
I
Scheme 2 Cyclization of N-aryl-2-aminopyridines 1 with 2-iodobenzo-
ic acids 2. Reagents and conditions: 1 (0.20 mmol), 2 (0.26 mmol),
Pd(OAc)2 (0.1 mol%), Ag2O (0.7 equiv), H2O (1.0 mL), 3 h. Isolated yields
are reported.
7
N
H
N
O
N
I
H2O, 120 °C, 3 h
+
(e)
N
II
Pd
CO2H
AcO
2
Finally, the pyridyl directing group was removed by a
two-step quaternization/hydride-reduction process at
room temperature to furnish phenanthridine-6-one (6) in
3a, 91%
I
2a
Scheme 4 Protecting group removal and control experiments
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

D
X. Ding et al.
Letter
Synlett
Based on our experimental results and previous studies,
the tentative mechanism shown in Scheme 5 is proposed.
The first step most probably involves coordination of Pd(II)
to the nitrogen atom of the pyridine substrate; this is fol-
lowed by a chelate-directed C−H activation to form the six-
membered palladacycle dimer complex I. Next, a carboxyl-
ate-directed oxidative addition18 affords the Pd(IV) species
II. Then Ag2O-mediated reductive elimination generates the
ortho-arylated product 8, which undergoes intramolecular
acylation to give 3a.
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H
N
Pd(OAc)2
AgI
+
N
NH
1a
8
N
HO2C
Ag2O
H
N
N
H
N
O
N
N
IV
Pd
I
L
N
O
II
3a
Pd
AcO
I
2
O
II
I
CO2H
(4) (a) Iwasaki, H.; Eguchi, T.; Tsutsui, N.; Ohno, H.; Tanaka, T. J. Org.
Chem. 2008, 73, 7145. (b) Bernini, R.; Cacchi, S.; Fabrizi, G.;
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X.; Yan, Y.; Ding, C. Eur. J. Org. Chem. 2012, 669. (g) Yu, Q.; Zhang,
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2a
Scheme 5 Proposed reaction mechanism
In conclusion, we have developed the first palladium-
catalyzed cyclization of N-aryl-2-aminopyridines with 2-
iodobenzoic acids through C–H bond activation in water for
the synthesis of phenanthridinones. It is interesting to note
that the reaction employs very low catalyst loadings (down
to 0.1 mol% Pd), and that water is the most effective solvent
in this catalytic reaction. More mechanistic details and fur-
ther studies on the scope of the substrates and applications
of the reaction are currently being investigated in our labo-
ratory.
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2013, 49, 173. (b) Liang, Z.; Zhang, J.; Liu, Z.; Wang, K.; Zhang, Y.
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G.; Xi, C. J. Org. Chem. 2016, 81, 6672. (e) Rao, D. N.; Rasheed, S.;
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Chem. Commun. 2017, 53, 1908. (g) Ling, F.; Zhang, C.; Ai, C.; Lv,
Y.; Zhong, W. J. Org. Chem. 2018, 83, 5698. (h) Gao, Y.; Cai, Z.; Li,
S.; Li, G. Org. Lett. 2019, 21, 3663.
Funding Information
Financial support for this study from the Jiangsu Synergetic Innova-
tion Center for Advanced Bio-Manufacture (NO.XTE1826) and the
Natural Science Research of Jiangsu Higher Education Institutions of
China (19KJB150027) is gratefully acknowledged.
N
aturalS
c
i
e
n
c
e
R
esearc
h
ofJi
a
n
gsu
H
i
g
h
er
E
d
u
c
ati
o
nInstituti
o
nsof
C
h
i
n
a
(1
9
K
J
B
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0
0
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Eur. J. Org. Chem. in press; DOI: 10.1002/ejoc.201900536.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691538.
S
u
p
p
orti
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gInformati
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n
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p
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orit
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gInformati
o
n
References and Notes
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(16) Phenanthridinones 3; General Procedure
Pd(OAc)2 (4.5 mg, 0.02 mmol) was dissolved in CH2Cl2 (1 mL)
and 10 L of the solution was added to a Schlenk tube equipped
with a Teflon-coated magnetic stirrer bar. The solvent was then
evaporated under high vacuum. The appropriate N-aryl-2-ami-
nopyridine 1 (0.20 mmol), 2-iodobenzoic acid 2 (0.26 mmol),
and Ag2O (32 mg, 0.14 mmol) were added to the Schlenk tube.
Water (1.0 mL) was added, the tube was placed in a preheated
oil bath (120 °C), and the mixture was stirred for 3 h. When the
reaction was complete, the reaction tube was allowed to cool to
r.t. and EtOAc was added. The organic layer was separated, and
the aqueous layer was washed with EtOAc. The filtrate was con-
centrated under reduced pressure, and the crude product was
purified by flash column chromatography (silica gel).
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5-Pyridin-2-ylphenanthridin-6(5H)-one (3a)
White solid; yield: 50 mg (93%); mp 185–186 °C. 1H NMR (400
MHz, CDCl3):  = 8.77 (d, J = 4.1 Hz, 1 H), 8.53 (d, J = 7.9 Hz, 1 H),
8.27–8.22 (m, 2 H), 7.97–7.93 (m, 1 H), 7.76–7.73 (m, 1 H),
7.57–7.53 (m, 1 H), 7.46–7.42 (m, 2 H), 7.28–7.21 (m, 2 H), 6.51
(d, J = 8.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3):  = 161.7, 151.9,
150.6, 139.3, 138.2, 134.2, 133.0, 129.1, 128.8, 128.1, 125.7,
124.8, 124.1, 123.1, 122.9, 121.9, 118.9, 116.4. HRMS (ESI-TOF):
m/z [M + H]+ calcd for C18H13N2O: 273.1028; found: 273.1036.
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© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E