Synthesis of Phenanthridin-6(5 H)-ones via Copper-Catalyzed Cyclization of 2-Phenylbenzamides

Article abstract of DOI:10.1055/s-0032-1316898

Synthesis of phenanthridin-6(5H)-ones was achieved via copper-catalyzed cyclization of 2-phenylbenzamides using air as the oxidant and KOt-Bu as the base. It was discovered that, besides Ph₃P, other ligands such as 1,10-phenanthroline, TMEDA as well as l-proline could also be used as the ligand to effect the transformation. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0032-1316898

1016▌
LETTER
lSetyternthesis of Phenanthridin-6(5H)-ones via Copper-Catalyzed Cyclization of
2-Phenylbenzamides
Synthesis of Phenanthridin-6(5H)-ones
Qingwen Gui,a Zhiyong Yang,a Xiang Chen,a Jidan Liu,a Ze Tan,*a Ruqing Guo,a Wei Yu*b
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. of China
E-mail: ztanze@gmail.com
b
Pharmaceutical Department, Kunming General Hospital of PLA, Kunming Yunnan 60032, P. R. of China
E-mail: kmweiyu@163.com
Received: 25.01.2013; Accepted after revision: 12.03.2013
Pd hydride from the adduct, the desired phenanthridin-6-
Abstract: Synthesis of phenanthridin-6(5H)-ones was achieved via
ones are formed. Murakami used Pd(TFA)2 as the cata-
copper-catalyzed cyclization of 2-phenylbenzamides using air as
lyst, O2 as the oxidant and inexpensive benzoic acid as the
additive while Dong used Pd(OAc)2 as the catalyst and
the oxidant and KOt-Bu as the base. It was discovered that, besides
Ph3P, other ligands such as 1,10-phenanthroline, TMEDA as well as
L-proline could also be used as the ligand to effect the transforma- Na2S2O8 as the oxidant. Both protocols are very easy to
tion.
run and do not require the use of any special equipment. It
should be emphasized that in this reaction, neither aryl ha-
lides nor aryl metals are required. Instead, the reaction re-
lies solely on the Pd-catalyzed C–H activations, making
this route extremely efficient. The method developed by
Wang is just as attractive (Scheme 1, equation 4). By
treating benzamides with iodobenzene in the presence of
a catalytic amount of Pd catalyst, the phenanthridin-6-
ones are produced in a single transformation though the
transformation actually involves multisteps including C–H
activation, oxidative insertion of iodobenzene by the
formed palladacycle, reductive elimination and another
round of C–H activation and C–N bond formation through
reductive elimination. In this reaction, two C–H bonds
and one N–H bond are cleaved and two new bonds, i.e., a
C–C bond and a C–N bond are formed, thus making this
route extremely attractive as well.
Key words: phenanthridin-6(5H)-ones, Cu-catalyzed, cyclization,
2-phenylbenzamides, air
Phenanthridin-6(5H)-ones are important structural motifs
in organic chemistry because they are widely present in
many natural products and medicinally active com-
pounds.1 Though the synthesis of phenanthridin-6(5H)-
ones has been reported as early as the beginning of the
20th century,2 it was not until the discovery of palladium-
catalyzed cross-couplings3 in the late 1970s that general
routes to diversely substituted phenanthridin-6(5H)-ones
have been developed. Typically, the C–C bond between
the two aryls is formed either through Pd-catalyzed carbo-
palladation–cyclization of N-(2-halophenyl)benzamide
(Scheme 1, equation 1)4 or through Pd-catalyzed cross-
coupling between aryl halides and aryl metals or metal
equivalents (Scheme 1, equation 2).5 In some cases, the
homocoupling of aryl bishalides was used too (Scheme 1,
equation 2).6 It should be noted that the C–N bond be-
tween the nitrogen atom and the benzene ring can be
formed through Buchwald–Hartwig amination reaction as
well.7 Though these strategies have provided convenient
ways for the synthesis of phenanthridin-6(5H)-ones, the
recently reported methods developed independently by
Murakami8a and Dong8b and Wang9 are revolutionary.10
The route developed by Murakami and Dong uses N-
phenylbenzamides as the starting materials (Scheme 1,
equation 3). Under Pd catalysis, the formation of the bia-
ryl C–C bond is achieved through Pd-catalyzed amide di-
rected C–H activation to form a five-membered
palladacycle. Then the in situ formed palladacycle under-
goes intramolecular carbopalladation to add the C–Pd
bond to the adjacent phenyl ring. After the elimination of
O
O
cat. Pd
NH
NH
(1)
X
X
M(X)
O
O
O
O
NH
NH
cat. Pd
NH
NH
(2)
(3)
cat. Pd
oxidant
O
O
cat. Pd
oxidant
OMe
OMe
+
I
N
H
N
(4)
one-pot
SYNLETT 2013, 24, 1016–1020
Advanced online publication: 28.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316898; Art ID: ST-2013-W0083-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

LETTER
Synthesis of Phenanthridin-6(5H)-ones
1017
Though the syntheses of phenanthridin-6(5H)-ones via desired phenanthridin-6(5H)-one in yields of 65% and
Pd-catalyzed cross-couplings are very versatile, one ma- 75%, respectively (Table 1, entries 11–13). Control reac-
jor weakness associated with these methods is the high tions also showed that the reaction did not take place with-
cost of Pd catalyst. Consequently, chemists are trying to out the Cu catalyst or oxygen, indicating both are essential
develop C–C bond formations and C–X bond formations for the reaction (not shown in Table 1). On the basis of
using inexpensive metal catalyst such as Ni,11 Cu,12 and these results, we decided to set reacting the 2-phenylben-
Fe13 complexes. Inspired by a recent report by Cacchi14 zamides with two equivalents of KOt-Bu, 0.1 equivalent
that quinolones can be readily synthesized via copper-cat- of CuI and 0.2 equivalent of Ph3P under a balloon of air at
alyzed intramolecular cyclization of 3,3-diarylacryl- 120 °C as our standard conditions.
amides (Scheme 2, equation 1), we wondered if
phenanthridin-6(5H)-ones could be synthesized in a simi-
Table 1 Reaction Condition Optimizationa
lar manner using 2-phenylbenzamides as the starting ma-
O
O
terials (Scheme 2, equation 2). Herein we report that by
using CuI as the catalyst and O2 as the oxidant, phenanth-
ridin-6(5H)-ones can be synthesized in good to excellent
yields from 2-phenylbenzamides.
NH2
NH
CuI, ligand
base
solvent
1
2
Ar2
Ar2
Entry Ligand
Base
Temp Solvent
(°C)
Yield
(%)b
cat. Cu, ligand
base, O2
Ar1
(1)
Ar1
1
2
Ph3P
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
Na2CO3
K2CO3
110
110
110
110
120
110
80
toluene
68
H2N
O
N
O
H
Ph3P
1,4-dioxane 72
O
O
cat. Cu, ligand
base, O2
3
Ph3P
DMF
20
trace
90
86
71
0
NH2
NH
(2)
this work
4
Ph3P
DMSO
5
Ph3P
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
Scheme 2
6
Ph3P
7
Ph3P
At the outset of our study, we decided to use the cycliza-
tion of 2-phenylbenzamide (1) as the model reaction. It is
worthwhile to point out that the synthesis of phenanthri-
din-6(5H)-one from N-tosyl 2-phenylbenzamide was re-
cently achieved by Fabis15 with Pd catalysis. Our reaction
started with the unsubstituted 2-phenylbenzamide which
was easily prepared by ortho-arylation of benzamides
with aryl iodide using methods reported by Daugulis16 and
Wang.17 When 0.5 mmol of 2-phenylbenzamide (1) was
treated in a sealed pressure tube with two equivalents of
KOt-Bu in the presence of 0.05 mmol of CuI (10 mol%)
and 0.1 mmol of Ph3P (20 mol%) under a balloon of air in
toluene at 110 °C for 18 hours, much to our delight, the
desired phenanthridin-6(5H)-one (2) was isolated in 68%
yield (Table 1, entry 1). Changing the solvent to 1,4-diox-
ane increased the yield to 72% while the use of DMSO or
DMF as the solvent gave disappointing results (Table 1,
entries 2–4). However, when the solvent was switched to
o-xylene, an excellent yield (90%) was obtained (Table 1,
entry 5). Decreasing the reaction temperature to 110 °C
dropped the yield slightly while running the reaction at 80
°C caused a sizable drop in the yield (Table 1, entries 6
and 7). Replacing KOt-Bu with Na2CO3, K2CO3 or
Cs2CO3 all led to no reaction (Table 1, entries 8–10). This
suggested that a strong base is necessary for this reaction
to proceed. On the other hand, substituting the Ph3P ligand
with other non-phosphorus ligand gave good results. For
example, the use of TMEDA as the ligand gave an 89%
yield while 1,10-phenanthroline and L-proline gave the
8
Ph3P
110
110
110
110
120
120
9
Ph3P
0
10
11
12
13
Ph3P
Cs2CO3
KOt-Bu
KOt-Bu
KOt-Bu
0
1,10-Phen
TMEDA
L-proline
65
89
75
a Unless specified otherwise, all reactions were carried out under a
balloon of air by treating 1 (0.5 mmol) at 120 °C with CuI (0.1 equiv),
Ph3P (0.2 equiv), and base (2 equiv) in o-xylene (3 mL) for 18 h.
b Isolated yields.
With the optimized conditions in hand, we decided to ex-
plore the scope and limitation of this reaction. Starting
from various 2-phenylbenzamides, a variety of phenanth-
ridin-6(5H)-ones were synthesized in yields ranging from
40–92% and the results are summarized in Table 2. From
the table, we can see good to excellent yields were ob-
tained with methyl- or methoxy-substituted 2-phenylben-
zamides (Table 2, entries 1–7 and 9–13). In contrast, when
an electron-withdrawing group such as nitro group was in-
troduced on the 4-position of the benzamide, the desired
product was only formed in trace amount (not shown in
Table 2). These results suggested that the reaction may in-
volve an electrophilic intermediate and the electron-
donating ability of the substituents may help to stabilize
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1016–1020

1018
Q. Gui et al.
LETTER
Table 2 Synthesis of Phenanthridin-6(5H)-ones via Copper-Catalyzed Cyclization of 2-Phenylbenzamidesa
O
O
CuI, Ph3P
KOt-Bu
NH
R1
NH2
R1
R2
o-xylene 120 °C
R2
Entry
R1
R2
Product
Yield
(%)b
Entry
R1
R2
Product
Yield
(%)b
O
O
NH
NH
O
1
3-Me
4-Me
78
9
H
3,5-Me2
78
O
MeO
NH
NH
NH
NH
2
3
4
5
3-MeO
4-MeO
4-Me
4-Me
85
78
88
87
10
11
12
13
H
4-MeO
92
88
82
73
OMe
O
O
O
NH
O
3,4-Me2
3-MeO
H
H
MeO
MeO
MeO
NH
NH
3,5-(MeO)2 4-Me
MeO
MeO
O
O
MeO
NH
3,4-Me2
4-Me
H
4-Me
4-Me
4-Me
4-Cl
4-MeO 4-Cl
MeO
Cl
O
O
O
NH
NH
NH
6
7
8
75
91
40
14
15
16
4-Me
3-Me
4-Cl
4-Cl
4-Cl
3-Me
43
45
55
Cl
O
NH
Cl
O
O
NH
NH
H
Cl
Cl
a Unless specified otherwise, all reactions were carried out under a balloon of air by treating 1 (0.5 mmol) at 120 °C with CuI (0.1 equiv), Ph3P
(0.2 equiv), and KOt-Bu (2 equiv) in o-xylene (3 mL) for 18 h.
b Isolated yields.
Synlett 2013, 24, 1016–1020
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Phenanthridin-6(5H)-ones
1019
the intermediate, thus facilitating the reaction. Chloro at- air to Cu(II) species. Then base-promoted reaction of the
oms could be tolerated on the benzene ring as well, how- benzamide with the Cu catalyst affords Cu amide A. The
ever, the yields dropped significantly for some cases oxidation and transmetallation sequence can be reversed
(entries 8 and 14–16). We surmise that side reactions such as well. Subsequent electrophilic attack of the benzene
as copper-catalyzed amidation of the carbon–chlorine ring by the Cu center in intermediate A will give interme-
bond may have taken place. If the desired cyclization is diate B. After base-promoted elimination of proton from
too slow, the amidation reaction can take over as the main the intermediate B, the benzene ring is reformed and the
reaction pathway. As a matter of fact, bromo-substituted desired phenanthridin-6(5H)-one is produced after reduc-
benzamides gave even lower yields (not shown in the ta- tive elimination.
ble). This is to be expected since the reactivity of C–Br
bonds is much higher than that of the corresponding C–Cl
O
bonds.
NH2
O
In order to see whether N-alkyl 2-phenylbenzamides are
suitable substrates or not, we synthesized 3 using Wang’s
procedure as well.17 However, reacting 3 under our stan-
dard reaction conditions did not give any desired product
at all (Scheme 3, equation 1). Instead all the starting ma-
terials remained intact. This means both hydrogen atoms
on the nitrogen atom are needed for the cyclization to pro-
ceed. Since one possible reaction intermediate is nitrene,18
we tested simple benzamide under our standard condi-
tions. The hypothesis is that if nitrene is indeed formed in
the reaction, it could undergo rearrangement to produce
isocynates which can react further with tert-butyl alcohol
to form carbamate. When benzamide was treated with CuI
(0.1 equiv), Ph3P (0.2 equiv) and KOt-Bu (2 equiv) in o-
xylene under air at 120 °C for 12 hours, most of the start-
ing benzamide remained unchanged (Scheme 3, equation
2). This suggested that the reaction may not be nitrene-
based. We also tested the cyclization of 1 using two equiv-
alents of CuCl2 or Cu(OAc)2 under N2. After regular
workup, the desired product 2 was isolated in 51% and
57% yield, respectively (Scheme 3, equation 3). This sug-
gested that the active intermediate in the critical cycliza-
tion step may be a Cu(II) species.
base
NH Cu
Cu(II)
A
O
Cu(I)
O
reductive elimination
O
NH
NH
Cu
NH
Cu
+
base
B
Scheme 4 Possible reaction mechanism
In summary, we have developed a copper-catalyzed ap-
proach for the preparation of phenanthridin-6(5H)-ones
from 2-phenylbenzamides20 which is based on intramo-
lecular C–H functionalization/N–H bond-forming pro-
cesses. The coupling reaction was found to the best run in
o-xylene under air at 120 °C using CuI/Ph3P as the cata-
lyst and KOt-Bu as the base. Our procedure is simple to
run, uses readily available starting materials and an inex-
pensive catalyst system. Detailed mechanistic investiga-
tions on this reaction are still ongoing and the results will
be reported in due course.
O
O
NHEt
NHEt
(1)
standard conditions
standard conditions
S.M. remained
Acknowledgment
4
3
O
H
Z. Tan would like to thank the National Science Foundation of Chi-
na (No. 21072051), NCET program (NCET-09-0334) and the Fun-
damental Research Funds for the Central Universities, Hunan
University, for financial support.
N
O
(2)
t-Bu
NH2
NH2
not formed
O
S.M. remained
O
O
NH
Cu(II) salt (2 equiv)
N2
Supporting Information Experimental procedures, characte-
rization data, and copies of 1H NMR and 13C NMR spectra for this
article are available online at http://www.thieme-con-
(3)
CuCl2 51%
Cu(OAc)2 57%
2
1
nect.com/ejournals/toc/synlett.SnuIpgfori
m
p
nirtSatnoIufprgmoiotrait
n
Scheme 3
References and Notes
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4. In the reaction mixture, Cu(I) catalyst is oxidized by the
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1016–1020

1020
Q. Gui et al.
LETTER
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(26.2 mg, 0.10 mmol) in anhyd o-xylene (3.0 mL) were
added 2-phenylbenzamide (1; 99 mg, 0.5 mmol) and KOt-
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to the system and the mixture was heated at 120 °C for 18 h.
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Et2O (25 mL) and H2O (25 mL). The aqueous layer was
extracted with Et2O (3 × 25 mL). The organic layers were
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removed under reduced pressure. The residue was purified
by flash column chromatography on silica gel (petroleum
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Synlett 2013, 24, 1016–1020
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