Copper(II)-mediated cascade oxidative C-C coupling and aromatization: Synthesis of 3-hydroxyphenanthridinone derivatives

Article abstract of DOI:10.1055/s-0032-1316542

A novel copper(II) acetate mediated synthesis of 3-hydroxyphenanthridin- 6(5H)-ones from N-(3-oxocyclohex-1-enyl)benzamides was developed. The process is postulated to involve an intramolecular oxidative C(sp²)-C(sp ³) bond formation

Full text of DOI:10.1055/s-0032-1316542

2374▌
PAPER
paper
Copper(II)-Mediated Cascade Oxidative C–C Coupling and Aromatization:
Synthesis of 3-Hydroxyphenanthridinone Derivatives
Synthesis of 3-Hydroxyphenanthridinone Derivatives
Qingzhen Yu, Nan Zhang, Yang Tang, Hang Lu, Jianhui Huang, Songqing Wang, Yunfei Du,* Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin 300072, P. R. of China
Fax +86(22)27404031; E-mail: duyunfeier@tju.edu.cn; E-mail: kangzhao@tju.edu.cn
Received: 23.03.2012; Accepted after revision: 15.05.2012
O
O
Abstract: A novel copper(II) acetate mediated synthesis of
3-hydroxyphenanthridin-6(5H)-ones from N-(3-oxocyclohex-1-
enyl)benzamides was developed. The process is postulated to in-
volve an intramolecular oxidative C(sp2)–C(sp3) bond formation
followed by dehydrogenative aromatization.
OH
NH
NH
OH
HO
OH
HO
HN
HO
OH
HO
phenanthridinone
Key words: copper(II) acetate, phenanthridinone, C–H functional-
ization, C–C oxidative coupling, dehydrogenative aromatization
O
diaza ellagic acid
Figure 1 Representative biologically active products containing the
phenanthridin-6(5H)-one skeleton
The transition-metal-mediated functionalization of C–H
bonds is a highly effective strategy for the construction of
C–C bonds.1 In most of these cross-dehydrogenative cou-
pling reactions, the application of expensive rhodium, ru-
thenium, and palladium catalysts for the conversion of C–
H bonds into C–C bonds has become a topic of intense in-
terest.2 During the past few years, inexpensive and less ex-
otic copper reagents, including both Cu(I)3 and Cu(II)4
salts, have also been successfully applied to C–H activa-
tion and subsequent C–C formation reactions. However,
only a few of these examples describe the copper(II)-
mediated cross coupling of C(sp2)–H and C(sp3)–H cen-
ters.4d,e
diated oxidative coupling under identical conditions to af-
ford the C(sp2)–C(sp3) coupling product C through the
intermediate B (Scheme 2). We postulate that the steric
hindrance brought by the N-phenyl ring might benefit the
approaching of the N-benzoyl ring to the enone ring, in
addition to blocking the formation of the unexpected car-
bazolone ring.
O
O
Pd(OAc)2, O2
AcOH, 100 °C
1 h, 81%
The phenanthridinones are an important class of heterocy-
cle that can be found in some biologically active natural
products5 (Figure 1). Direct oxidative C–C coupling be-
tween the two aryl rings of N-phenylbenzamides is un-
doubtedly a promising synthetic strategy for the formation
of this class of compounds. Both palladium(II) acetate and
hypervalent iodine(III) reagent have been used to realize
this oxidative C–C coupling process.6 Herein, we describe
an alternative synthesis of 3-hydroxyphenanthridin-
6(5H)-one through copper(II)-mediated intramolecular
oxidative C(sp2)–C(sp3) bond formation followed by de-
hydrogenative aromatization.
N
Me
I
N
Me
II
Scheme 1 Previous synthesis of N-alkylcarbazolones via palladi-
um(II)-mediated oxidative C(sp2)–C(sp2) bond coupling
N-Benzoylated enaminone 1a can be readily prepared
through the condensation of cyclohexane-1,3-dione with
2,6-dimethylaniline,8 followed by the amide formation
from benzoyl chloride with the resultant N-aryl enami-
none.9 With 1a in hand, we initiated our study by examin-
ing the feasibility of our proposal shown in Scheme 2.
Subjecting 1a to identical conditions [Pd(OAc)2/O2,
AcOH, 100 °C] for the preparation of carbazolone II gave
phenanthridinone 2a in 21% yield, without any formation
of the proposed product C (Table 1, entry 1). This result
clearly showed that not only the expected C(sp2)–C(sp3)
bond formation occured, but that the dehydrogenative aro-
matization was also concurrently realized.
In a previous study, we reported that N-methylcarbazo-
lone II can be synthesized from N-methyl-substituted 3-
(arylamino)cyclohex-2-enone I by intramolecular oxida-
tive coupling mediated by palladium(II) acetate under an
oxygen atmosphere (Scheme 1).7 Inspired by this, we en-
visaged that the N-benzoylated substrate 1a, under acidic
conditions, can be tautomerized to its resonance structure
A, which may undergo the same palladium(II) acetate me-
Inspired by the C–H activation conditions of Glorius and
co-workers for the synthesis of indoles,10 copper(II) ace-
tate was examined as the oxidant and 2a was obtained in
a relatively better yield (Table 1, entry 2). The subsequent
control experiment revealed that the reaction in the ab-
SYNTHESIS 2012, 44, 2374–2384
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DOI: 10.1055/s-0032-1316542; Art ID: SS-2012-H0300-OP
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of 3-Hydroxyphenanthridinone Derivatives
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Table 1 Condition Screening for the Synthesis of 3-Hydroxyphen-
anthridin-6(5H)-ones 2a from N-Benzoylated Enaminone 1aa
O
O
O
OH
Pd(II), oxidant
solvent
N
N
oxidant, base
O
O
N
N
solvent, temp, air
C
1a
O
O
OH
O
1a
2a
oxidative
C–C coupling
Entry Catalyst
Equiv Base
Solvent
Time Yieldb
(h)
(%)
N
N
1c
2d
Pd(OAc)2
0.1
–
AcOH
DMF
5.0
1.0
21
53
O
O
Pd(OAc)2/ 0.1/2.2 K2CO3
Cu(OAc)2
A
B
Scheme 2 Proposed pathway for the palladium(II)-mediated oxida-
tive formation of C–C bonds
3d
4
Cu(OAc)2 2.2
Cu(OAc)2 2.2
Cu(OAc)2 2.2
Cu(OAc)2 2.2
Cu(OAc)2 2.2
Cu(OAc)2 2.2
Cu(OAc)2 2.2
Cu(OAc)2 2.2
Cu(OAc)2 2.2
Cu(OAc)2 2.2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
2.5
0.5
0.2
52
68
64
sence of palladium(II) acetate afforded a similar yield of
phenanthridinone 2a, which implied that copper(II) ace-
tate played a decisive role and palladium(II) acetate was
not indispensable in this process (entry 3). Moreover, the
reaction operated at 130 °C gave a promising 68% yield
within 30 minutes, while more byproducts were formed at
100 °C due to the longer reaction time and no improve-
ment in yield was observed at 150 °C (entries 3–5). Sol-
vent screening showed that N,N-dimethylacetamide
(DMA) was a better solvent than N,N-dimethylform-
amide, while p-xylene, chlorobenzene, and ethylene gly-
col were unsuitable solvents (entries 4 and 6–9). Further
optimization of the base revealed that cesium carbonate
was the most efficient (entries 9–12). Other copper(II) ox-
idants, such as copper(II) chloride or copper(II) bromide,
were also tested but did not provide better results (entries
13, 14). It is worth noting that copper(I) iodide was also
effective for the process, albeit the desired product 2a was
obtained in only 39% yield (entry 15). This result might
imply that air acts as co-oxidant that can convert Cu(I)
back into Cu(II) species. It can be further supported by the
fact that 2.2 equivalents of copper(II) acetate were actual-
ly sufficient for the consumption of the substrate, while
theoretically, 4.0 equivalents of copper(II) acetate would
be required (entry 16). However, when the reaction was
carried out using 0.5 equivalents of copper(II) acetate un-
der an oxygen atmosphere, the reaction time was greatly
prolonged and the yield of 2a was sharply reduced to 32%
due to the formation of more byproducts (entry 17). Non-
metallic hypervalent iodine oxidants such as phenylio-
dine(III) diacetate (PIDA) and phenyliodine(III) bis(tri-
fluoroacetate) (PIFA) were also investigated.11 However,
neither provided better results than copper(II) acetate for
this cross-coupling and dehydrogenative reaction (entries
18–20).
5e
g
6
p-xylene 10
–
g
7
PhCl
EG
10
5.0
0.5
0.5
0.5
12
10
2.0
2.0
0.2
3.0
30
3
–
8f
30
74
80
52
22
9
DMA
10
11
12
13
14
15
16
17c
18i
19i
20i
Cs2CO3 DMA
KOH
Et3N
DMA
DMA
h
CuCl2
CuBr2
CuI
2.2
2.2
2.2
Cs2CO3 DMA
Cs2CO3 DMA
Cs2CO3 DMA
Cs2CO3 DMA
Cs2CO3 DMA
–
32
39
Cu(OAc)2 4.0
Cu(OAc)2 0.5
78
32
PIDA
PIDA
PIFA
3.0
3.0
3.0
–
DMA
trace
29
Cs2CO3 DMA
Cs2CO3 DMA
h
1
–
a Reaction conditions: benzamide 1a (0.3 mmol), Cu salt (0.66
mmol), base (0.60 mmol), solvent (3.0 mL), 130 °C.
b Isolated yields.
c The reaction was carried out under an O2 atmosphere (using an O2
balloon) at 100 °C.
d The reaction was carried out at 100 °C.
e The reaction was carried out at 150 °C.
f EG = ethylene glycol.
g No reaction.
h No desired product.
i Reaction conditions: benzamide 1a (0.3 mmol), I(III) oxidants (0.9
mmol), base (0.60 mmol), solvent (3.0 mL), 130 °C.
Under the optimal conditions (Table 1, entry 10), we ex-
amined the substrate scope with different substituents on
the benzoyl ring of various N-(3-oxocyclohex-1-
© Georg Thieme Verlag Stuttgart · New York
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Q. Yu et al.
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Table 2 Copper(II) Acetate Mediated Conversion of N-Benzoylated
Enaminone 1 into 3-Hydroxyphenanthridin-6(5H)-onesa (continued)
enyl)benzamides. The substrates bearing both electron-
donating and electron-withdrawing groups in the para po-
sition of the benzoyl ring proceeded smoothly to provide
the corresponding phenanthridinones in acceptable to
good yields, which are not significantly influenced by the
electronic properties of the substituents (Table 2, entries
2–6). In the case of ortho-methyl-substituted enaminone
1g, the reaction afforded a comparably lower yield, possi-
bly because the presence of the ortho-methyl group blocks
the free rotation of the benzoyl ring (entry 7).
O
OH
Cu(OAc)2, Cs2CO3
N
N
DMA, 130 °C, air, 0.5 h
O
O
R
R
1
2
Entry
Substrate
Product
Yieldb
(%)
Table 2 Copper(II) Acetate Mediated Conversion of N-Benzoylated
Enaminone 1 into 3-Hydroxyphenanthridin-6(5H)-onesa
OH
O
O
OH
Cu(OAc)2, Cs2CO3
N
N
N
N
5
75
DMA, 130 °C, air, 0.5 h
O
O
O
O
R
R
Cl
Cl
1
2
1e
2e
Entry
Substrate
Product
Yieldb
(%)
OH
O
O
OH
N
N
6
72
O
O
N
O
N
O
1
80
CF3
CF3
1f
2f
O
OH
1a
2a
O
OH
N
N
7
52
O
O
N
N
2
71
O
O
1g
2g
O
OH
1b
2b
OH
O
N
66c
N
8
(56:44)
O
10
N
N
O
3
67
Cl
O
O
8
Cl
O
OMe
OMe
2h: 8-Cl/2h′: 10-Cl
1h
1c
2c
OH
O
OH
N
N
N
N
63c
9
4
78
O
10
(53:47)
O
O
O
OMe
8
F
F
OMe
2i: 8-OMe/2i′: 10-OMe
1d
2d
1i
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Synthesis of 3-Hydroxyphenanthridinone Derivatives
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Table 2 Copper(II) Acetate Mediated Conversion of N-Benzoylated
Enaminone 1 into 3-Hydroxyphenanthridin-6(5H)-onesa (continued)
2,6-dimethylphenyl substituent to a less bulky phenyl or
benzyl group,12 the reaction afforded the phenanthridi-
none products 2n (confirmed through X-ray crystallo-
graphic analysis, see Figure 2) and 2o in decreased yields,
respectively, with concomitant formation of other uniden-
tified polar byproducts (Scheme 3). These results clearly
implied that steric hindrance effected by the substituent on
the N-atom in the substrate is a crucial factor influencing
the outcome of the reaction.
O
OH
Cu(OAc)2, Cs2CO3
N
N
DMA, 130 °C, air, 0.5 h
O
O
R
R
1
2
Entry
Substrate
Product
Yieldb
(%)
OH
O
N
O
N
O
10
71
CF3
CF3
1j
2j
O
OH
N
N
11
70d
O
O
OMe
OMe
OMe
OMe
Figure 2 X-ray crystal structure of 2n
1k
2k
a Reaction conditions: benzamide 1 (0.3 mmol), Cu(OAc)2 (0.66
mmol), Cs2CO3 (0.60 mmol), DMA (3.0 mL), stirring, 130 °C, air, 0.5
OH
O
h.
b Isolated yields.
R
O
R
O
Cu(OAc)2, Cs2CO3
DMA, 130 °C, air
c Ratio of isomers was determined by 1H NMR.
d Overall yield of two isomers, with the other regioisomer being iso-
lated in 7% yield.
N
N
1l–o
2l–o
The presence of a meta-substituent in the benzoyl ring has
the possibility of generating two regioisomeric products.
In our studies, the substrates with both meta-chloro and
meta-methoxy groups were found to give an inseparable
regioisomeric mixture, with no obvious regioselectivity
being observed (entries 8, 9). However, the meta-trifluo-
romethyl-substituted enaminone 1j only afforded phenan-
thridinone product 2j as the sole regioisomer (entry 10).
As to the 3,4-dimethoxy-substituted substrate 1k, the re-
action gave the two separable regioisomers, with the less
steric 2k being predominantly formed (entry 11).
1l (R = 2,4-Me2C6H3)
1m (R = 2-MeC6H4)
1n (R = Ph)
2l (R = 2,4-Me2C6H3)
2m (R = 2-MeC6H4)
2n (R = Ph)
45%
43%
30%
24%
2o (R = Bn)
1o (R = Bn)
Scheme 3 Scope studies by changing the substituent on the N-atom
Notably, when N-(3-oxocyclohex-1-enyl)benzamide (1p)
was employed, the reaction produced a mixture of the
desired phenanthridinone 2p and the uncoupled 2p′
(Scheme 4). Subjecting 2p′ to identical conditions failed
to convert it into 2p,13 which suggested that the oxidative
C–C bond coupling took place prior to the dehydrogena-
tive aromatization step. In order to probe this possible
mechanistic sequence, we explored the coupling reaction
of substrate 1q, in which two methyl groups were intro-
duced into the cyclohexenone ring of 1a to prevent the
Further studies on the scope of this reaction revealed that
the 2,6-dimethylphenyl moiety in the substrate was bene-
ficial for a smooth reaction. Substrate 1l, differing from
1a by moving one ortho-methyl group to the para posi-
tion, afforded the product 2l in only 45% yield. Similarly,
a lower yield was also observed when the substrate bear-
ing only one ortho-methyl group was used. Changing the
© Georg Thieme Verlag Stuttgart · New York
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Q. Yu et al.
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O
OH
OH
OAc
Cu
CuOAc
O
O
O
OAc
Cu(OAc)2, Cs2CO3
DMA, 130 °C, air
HN
O
HN
HN
– Cu(I)
Ar
+
Ar
N
N
N
•
H
O
O
base
O
O
O
1p
2p (15%)
2p' (20%)
1a
D
E
Scheme 4 The reaction of the N-unsubstituted N-benzoyl enaminone
O
O
O
– H+
Cu(II)
Ar
Ar
Ar
Cu(II)
aromatization step occurring. As expected, the reaction
realized the C(sp2)–C(sp3) coupling and afforded the de-
sired product 3q in 42% yield (Scheme 5).
N
N
N
H
H
– H+ , – Cu(I)
– Cu(I)
O
O
O
+
•
F
G
H
O
O
O
O
Cu(OAc)2, Cs2CO3
N
– H+
N
Ar
Ar
Cu(II)
N
N
2a
+
DMA, 130 °C, air, 8 h
42%
•
– Cu(I)
O
O
O
O
1q
3q
Ar = 2,6-Me2C6H3
I
J
Scheme 5 The oxidative C(sp3)–C(sp2) coupling without aromatiza-
tion
Scheme 6 Proposed pathway for the oxidative coupling/dehydroge-
native aromatization process
As palladium is not necessary in the process, a single elec-
tron transfer (SET) mechanism14 is proposed (Scheme 6).
Firstly, the copper(II) intermediate D is formed from the
base-mediated reaction of substrate 1a with copper(II)
acetate by losing one molecule of acetic acid. The subse-
quent removal of CuOAc from D generates the carbon
radical intermediate E, which undergoes the cyclization
onto the aromatic ring to give the cyclohexadienyl radical
F. Mediated by copper(II) acetate, a second SET process
occurs to convert the radical intermediate F into carboca-
tion intermediate G. With the removal of a proton, the ox-
idative C(sp2)–C(sp3) cross coupling occurs to give H.
Further oxidation of H by copper(II) acetate adopts a sim-
ilar sequence to afford the radical intermediate I and then
the carbocation J. Finally, the rearomatization is realized
by the loss of a proton and the simultaneous keto–enol
isomerization.
exposure to UV light. The reagents and solvents were purchased as
reagent grade and were used without further purification. Flash col-
umn chromatography was performed over silica gel 200–300 mesh
using petroleum ether (PE) and EtOAc mixtures.
Substrates 1a–q were prepared following literature procedures.9,15
N-(2,6-Dimethylphenyl)-N-(3-oxocyclohex-1-enyl)benzamide
(1a)
Following the literature procedure,9c 1a was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
1.1182 g (35%); mp 157–158 °C; Rf = 0.38 (EtOAc–PE, 30:70).
1H NMR (400 MHz, DMSO-d6): δ = 7.53 (d, J = 7.5 Hz, 2 H, Harom),
7.44 (t, J = 7.0 Hz, 1 H, Harom), 7.35 (t, J = 7.5 Hz, 2 H, Harom), 7.12–
7.10 (m, 3 H, Harom), 5.00 (s, 1 H, CH), 2.71 (br s, 2 H, CH2), 2.30
(t, J = 6.0 Hz, 2 H, CH2), 2.18 (s, 6 H, CH3), 1.94–1.92 (m, 2 H,
CH2).
13C NMR (100 MHz, DMSO-d6): δ = 198.4, 170.2, 162.9, 139.5,
136.2, 135.7, 132.0, 129.5, 129.1, 128.6, 128.5, 117.6, 37.2, 29.6,
23.1, 18.3.
In summary, we have described a novel synthetic route to
3-hydroxyphenanthridin-6(5H)-ones by a cascade oxida-
tive C(sp2)–C(sp3) coupling and dehydrogenative aroma-
tization. The process is economic since the reaction is
mediated by the inexpensive copper(II) acetate and the
use of the palladium catalyst is not necessary. Although
the substitution pattern of the substrate is limited and the
yields need further improvement, the work might provide
some insights into the future study of copper(II)-mediated
reactions involving functionalization of C–H bond.
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H42N2NaO4: 661.3;
found: 661.4.
N-(2,6-Dimethylphenyl)-4-methyl-N-(3-oxocyclohex-1-
enyl)benzamide (1b)
Following the literature procedure,9c 1b was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
0.6985 g (21%); mp 169–170 °C; Rf = 0.37 (EtOAc–PE, 30:70).
1H NMR (400 MHz, DMSO-d6): δ = 7.42 (d, J = 7.5 Hz, 2 H, Harom),
7.16–7.11 (m, 5 H, Harom), 4.96 (s, 1 H, CH), 2.71 (s, 2 H, CH2), 2.30
(s, 2 H, CH2), 2.27 (s, 3 H, CH3), 2.17(s, 6 H, CH3), 1.95–1.92 (m,
2 H, CH2).
1H and 13C NMR spectra were recorded on a 400 MHz (100 MHz
for 13C NMR) spectrometer and reference to the internal standard to
TMS. Melting points were determined with a national micromelting
point apparatus without corrections. TLC plates were visualized by
13C NMR (100 MHz, DMSO-d6): δ = 198.4, 170.2, 163.2, 142.2,
139.8, 136.1, 132.9, 129.6, 129.2, 129.0, 128.7, 117.3, 37.2, 29.7,
23.2, 21.4, 18.3.
Synthesis 2012, 44, 2374–2384
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Synthesis of 3-Hydroxyphenanthridinone Derivatives
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LRMS (ESI): m/z [2 M + Na]+ calcd for C44H46N2NaO4: 689.3;
found: 689.5.
N-(2,6-Dimethylphenyl)-2-methyl-N-(3-oxocyclohex-1-
enyl)benzamide (1g)
Following the literature procedure,9c 1g was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
0.3668 g (11%); mp 119–121 °C; Rf = 0.38 (EtOAc–PE, 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.30–7.23 (m, 3 H, Harom), 7.16–
7.07 (m, 4 H, Harom), 5.30 (s, 1 H, CH), 2.51 (s, 3 H, CH3), 2.45 (br
s, 2 H, CH2), 2.33 (t, J = 6.5 Hz, 2 H, CH2), 2.25 (s, 6 H, CH3), 1.97–
1.91 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 199.0, 169.9, 161.8, 138.9, 137.7,
135.8, 135.2, 131.7, 130.5, 129.2, 128.6, 126.8, 125.2, 118.3, 37.0,
30.3, 23.3, 20.1, 18.3.
N-(2,6-Dimethylphenyl)-4-methoxy-N-(3-oxocyclohex-1-
enyl)benzamide (1c)
Following the literature procedure,9c 1c was purified by chromatog-
raphy (silica gel, 20% EtOAc–PE) to give a white solid; yield:
0.8042 g (23%); mp 161–162 °C; Rf = 0.38 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 7.50 (d, J = 8.0 Hz, 2 H, Harom),
7.19–7.14 (m, 3 H, Harom), 6.89 (d, J = 8.0 Hz, 2 H, Harom), 4.95 (s,
1 H, CH), 3.75 (s, 3 H, OCH3), 2.72 (br s, 2 H, CH2), 2.30 (t, J = 5.0
Hz, 2 H, CH2), 2.17 (s, 6 H, CH3), 1.94–1.93 (m, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 198.4, 169.7, 163.5, 162.3,
140.0, 136.1, 131.0, 129.6, 129.0, 127.6, 116.9, 114.0, 55.8, 37.2,
29.7, 23.2, 18.3.
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H46N2NaO4: 689.3;
found: 689.4.
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H46N2NaO6: 721.3;
found: 721.6.
3-Chloro-N-(2,6-dimethylphenyl)-N-(3-oxocyclohex-1-
enyl)benzamide (1h)
Following the literature procedure,9c 1h was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
0.9911 g (28%); mp 131–132 °C; Rf = 0.34 (EtOAc–PE, 30:70).
N-(2,6-Dimethylphenyl)-4-fluoro-N-(3-oxocyclohex-1-enyl)ben-
zamide (1d)
Following the literature procedure,9c 1d was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
0.6752 g (20%); mp 126–128 °C; Rf = 0.35 (EtOAc–PE, 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.47 (s, 1 H, Harom), 7.31 (d, J =
8.0 Hz, 1 H, Harom), 7.28 (d, J = 8.0 Hz, 1 H, Harom), 7.15 (t, J = 8.0
Hz, 1 H, Harom), 7.10 (d, J = 7.0 Hz, 1 H, Harom), 7.01 (d, J = 7.5 Hz,
2 H, Harom), 5.23 (s, 1 H, CH), 2.94 (t, J = 5.5 Hz, 2 H, CH2), 2.45
(t, J = 6.5 Hz, 2 H, CH2), 2.20 (s, 6 H, CH3), 2.12–2.06 (m, 2 H,
CH2).
13C NMR (100 MHz, CDCl3): δ = 199.3, 168.9, 162.7, 138.9, 136.9,
135.7, 134.1, 131.5, 129.5, 129.2, 129.1, 128.6, 126.1, 117.8, 37.3,
29.8, 23.4, 18.3.
1H NMR (400 MHz, DMSO-d6): δ = 7.59 (br s, 2 H, Harom), 7.21–
7.13 (m, 5 H, Harom), 5.00 (s, 1 H, CH), 2.73 (br s, 2 H, CH2), 2.32
(t, J = 6.0 Hz, 2 H, CH2), 2.18 (s, 6 H, CH3), 1.96–1.93 (m, 2 H,
CH2).
13C NMR (100 MHz, DMSO-d6): δ = 198.4, 169.1, 164.1 (d, JC-F
243.0 Hz), 162.8, 139.4, 136.2, 132.2 (d, JC-F = 2.0 Hz), 131.4 (d,
C-F = 9.0 Hz), 129.6, 129.1, 117.7, 115.7 (d, JC-F = 22.0 Hz), 37.2,
=
J
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H4035Cl2N2NaO4: 729.2;
found: 729.4.
29.5, 23.1, 18.3.
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H40F2N2NaO4: 697.3;
found: 697.7.
N-(2,6-Dimethylphenyl)-3-methoxy-N-(3-oxocyclohex-1-
enyl)benzamide (1i)
4-Chloro-N-(2,6-dimethylphenyl)-N-(3-oxocyclohex-1-
enyl)benzamide (1e)
Following the literature procedure,9c 1i was purified by chromatog-
raphy (silica gel, 20% EtOAc–PE) to give a white solid; yield:
0.7692 g (22%); mp 138–139 °C; Rf = 0.36 (EtOAc–PE, 40:60).
Following the literature procedure,9c 1e was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
0.7083 g (20%); mp 138–140 °C; Rf = 0.34 (EtOAc–PE, 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.15 (t, J = 8.0 Hz, 1 H, Harom),
7.09 (t, J = 8.0 Hz, 1 H, Harom), 7.06 (d, J = 9.5 Hz, 1 H, Harom), 7.01
(d, J = 7.0 Hz, 2 H, Harom), 7.00 (s, 1 H, Harom), 6.90 (d, J = 8.0 Hz,
1 H, Harom), 5.23 (s, 1 H, CH), 3.70 (s, 3 H, OCH3), 2.91 (t, J = 5.5
Hz, 2 H, CH2), 2.43 (t, J = 6.5 Hz, 2 H, CH2), 2.21 (s, 6 H, CH3),
2.11–2.04 (m, 2 H, CH2).
1H NMR (400 MHz, DMSO-d6): δ = 7.52 (d, J = 8.0 Hz, 2 H, Harom),
7.42 (d, J = 8.0 Hz, 2 H, Harom), 7.22–7.12 (m, 3 H, Harom), 5.01 (s,
1 H, CH), 2.73 (br s, 2 H, CH2), 2.32 (t, J = 6.0 Hz, 2 H, CH2), 2.18
(s, 6 H, CH3), 1.96–1.93 (m, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 198.4, 169.2, 162.6, 139.2,
136.6, 136.2, 134.5, 130.4, 129.6, 129.2, 128.8, 117.9, 37.2, 29.4,
23.1, 18.3.
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H4035Cl2N2NaO4: 729.2;
found: 729.4.
13C NMR (100 MHz, CDCl3): δ = 199.5, 170.1, 163.2, 159.1, 139.4,
136.4, 135.8, 129.4, 129.0, 128.8, 120.8, 118.0, 117.6, 113.4, 55.2,
37.3, 30.0, 23.4, 18.3.
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H46N2NaO6: 721.3;
found: 721.6.
N-(2,6-Dimethylphenyl)-N-(3-oxocyclohex-1-enyl)-4-(trifluoro-
methyl)benzamide (1f)
N-(2,6-Dimethylphenyl)-N-(3-oxocyclohex-1-enyl)-3-(trifluoro-
methyl)benzamide (1j)
Following the literature procedure,9c 1f was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
1.3947 g (36%); mp 126–128 °C; Rf = 0.35 (EtOAc–PE, 30:70).
Following the literature procedure,9c 1j was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
1.5502 g (40%); mp 142–143 °C; Rf = 0.36 (EtOAc–PE, 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.54 (d, J = 8.0 Hz, 2 H, Harom),
7.48 (d, J = 8.0 Hz, 2 H, Harom), 7.11 (t, J = 7.5 Hz, 1 H, Harom),
7.01(d, J = 7.5 Hz, 2 H, Harom), 5.24 (s, 1 H, CH), 2.99 (t, J = 5.5 Hz,
2 H, CH2), 2.46 (t, J = 6.5 Hz, 2 H, CH2), 2.21 (s, 6 H, CH3), 2.14–
2.08 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 199.3, 169.0, 162.5, 138.8, 138.6,
135.7, 132.9 (q, JC-F = 33.0 Hz), 129.6, 129.2, 128.5, 125.0 (q,
JC-F = 4.0 Hz), 123.4 (q, JC-F = 272.0 Hz), 118.0, 37.3, 29.7, 23.4,
18.2.
1H NMR (400 MHz, CDCl3): δ = 7.65 (s, 1 H, Harom), 7.64 (d, J =
9.5 Hz, 1 H, Harom), 7.58 (d, J = 8.0 Hz, 1 H, Harom), 7.37 (t, J = 8.0
Hz, 1 H, Harom), 7.10 (t, J = 7.5 Hz, 1 H, Harom), 7.01 (d, J = 7.5 Hz,
2 H, Harom), 5.24 (s, 1 H, CH), 3.00 (t, J = 5.5 Hz, 2 H, CH2), 2.47
(t, J = 6.5 Hz, 2 H, CH2), 2.20 (s, 6 H, CH3), 2.15–2.09 (m, 2 H,
CH2).
13C NMR (100 MHz, CDCl3): δ = 199.3, 168.9, 162.5, 138.8, 136.0,
135.7, 131.4, 130.4 (q, JC-F = 33.0 Hz), 129.5, 129.2, 128.6, 127.9
(q, JC-F = 4.0 Hz), 125.2 (q, JC-F = 4.0 Hz), 123.4 (q, JC-F = 273.0 Hz),
117.9, 37.3, 29.7, 23.4, 18.2.
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H40F6N2NaO4: 797.3;
found: 797.6.
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H40F6N2NaO4: 797.3;
found: 797.3.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2374–2384

2380
Q. Yu et al.
PAPER
N-(2,6-Dimethylphenyl)-3,4-dimethoxy-N-(3-oxocyclohex-1-
enyl)benzamide (1k)
1H NMR (400 MHz, DMSO-d6): δ = 7.61 (d, J = 7.0 Hz, 2 H, Harom),
7.51 (t, J = 7.0 Hz, 1 H, Harom), 7.45 (t, J = 7.0 Hz, 2 H, Harom), 7.38–
7.34 (m, 4 H, Harom), 7.27 (t, J = 6.5 Hz, 1 H, Harom), 5.48 (s, 1 H,
CH), 5.01 (s, 2 H, CH2), 2.37 (t, J = 5.0 Hz, 2 H, CH2), 2.10 (t, J =
6.0 Hz, 2 H, CH2), 1.69 (t, J = 6.0 Hz, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 198.7, 171.0, 162.9, 136.8, 136.0,
131.7, 128.8, 128.7, 128.0, 127.7, 127.4, 121.9, 52.6, 36.7, 31.4,
22.1.
Following the literature procedure,9c 1k was purified by chromatog-
raphy (silica gel, 20% EtOAc–PE) to give a white solid; yield:
1.0623 g (28%); mp 167–169 °C; Rf = 0.41 (EtOAc–PE, 50:50).
1H NMR (400 MHz, CDCl3): δ = 7.15 (dd, J = 8.5, 2.0 Hz, 1 H,
Harom), 7.10 (t, J = 8.5 Hz, 1 H, Harom), 7.02 (d, J = 7.5 Hz, 2 H,
Harom), 6.98 (d, J = 2.0 Hz, 1 H, Harom), 6.70 (d, J = 8.5 Hz, 1 H,
Harom), 5.21 (s, 1 H, CH), 3.85 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3),
2.95 (t, J = 6.0 Hz, 2 H, CH2), 2.45 (t, J = 6.5 Hz, 2 H, CH2), 2.20
(s, 6 H, CH3), 2.13–2.06 (m, 2 H, CH2).
LRMS (ESI): m/z [2 M + Na]+ calcd for C40H38N2NaO4: 633.3;
found: 633.4.
13C NMR (100 MHz, CDCl3): δ = 199.6, 169.7, 163.9, 151.9, 148.1,
140.0, 135.8, 129.4, 128.7, 127.1, 123.0, 117.1, 111.8, 110.0, 55.9,
55.7, 37.3, 30.1, 23.5, 18.3.
LRMS (ESI): m/z [2 M + Na]+ calcd for C46H50N2NaO8: 782.3;
found: 782.5.
N-(3-Oxocyclohex-1-enyl)benzamide (1p)
Following the literature procedure,9b 1p was purified by chromatog-
raphy (silica gel, 50% EtOAc–PE) to give a pale yellow solid; yield:
1.1123 g (76%); mp 171–172 °C; Rf = 0.38 (EtOAc–PE, 80:20).
1H NMR (400 MHz, DMSO-d6): δ = 10.02 (s, 1 H, NH), 7.87 (d, J =
7.5 Hz, 2 H, Harom), 7.62 (t, J = 7.0 Hz, 1 H, Harom), 7.53 (t, J = 7.5
Hz, 2 H, Harom), 6.78 (s, 1 H, CH), 2.64 (t, J = 5.5 Hz, 2 H, CH2),
2.26 (t, J = 6.0 Hz, 2 H, CH2), 1.95–1.92 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 200.0, 166.3, 156.2, 133.9, 132.5,
128.8, 127.4, 112.5, 36.7, 28.6, 21.7.
N-(2,4-Dimethylphenyl)-N-(3-oxocyclohex-1-enyl)benzamide
(1l)
Following the literature procedure,9c 1l was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
1.3412 g (42%); mp 134–135 °C; Rf = 0.35 (EtOAc–PE, 30:70).
LRMS (ESI): m/z [2 M + Na]+ calcd for C26H26N2NaO4: 453.2;
found: 453.3.
1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.0 Hz, 2 H, Harom),
7.33 (t, J = 7.0 Hz, 1 H, Harom), 7.24 (d, J = 6.0 Hz, 2 H, Harom), 6.98
(s, 1 H, Harom), 6.86 (t, J = 7.5 Hz, 2 H, Harom), 5.28 (s, 1 H, CH),
2.98–2.76 (m, 2 H, CH2), 2.42 (t, J = 6.0 Hz, 2 H, CH2), 2.24 (s, 3
H, CH3), 2.19 (s, 3 H, CH3), 2.13–2.03 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 199.4, 170.8, 164.0, 138.5, 137.6,
135.4, 134.8, 132.4, 131.3, 129.1, 128.7, 128.1, 128.0, 119.0, 37.2,
29.8, 23.1, 21.0, 17.9.
N-(5,5-Dimethyl-3-oxocyclohex-1-enyl)-N-(2,6-dimethylphe-
nyl)benzamide (1q)
Following the literature procedure,9c 1q was isolated as purified by
chromatography (silica gel, 15% EtOAc–PE) to give a pale yellow
solid; yield: 0.5212 g (15%); mp 106–108 °C; Rf = 0.39 (EtOAc–
PE, 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 7.5 Hz, 2 H, Harom),
7.33 (t, J = 7.5 Hz, 1 H, Harom), 7.22 (t, J = 7.5 Hz, 2 H, Harom), 7.07
(t, J = 7.5 Hz, 1 H, Harom), 7.00 (d, J = 7.5 Hz, 2 H, Harom), 5.21 (s,
1 H, CH), 2.88 (s, 2 H, CH2), 2.29 (s, 2 H, CH2), 2.22 (s, 6 H, CH3),
1.14 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 199.5, 170.9, 160.8, 139.2, 135.9,
135.4, 131.4, 129.3, 128.8, 128.2, 127.9, 116.4, 50.8, 43.1, 34.1,
28.4, 18.4.
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H42N2NaO4: 661.3;
found: 661.4.
N-(3-Oxocyclohex-1-enyl)-N-(o-tolyl)benzamide (1m)
Following the literature procedure,9c 1m was purified by chroma-
tography (silica gel, 15% EtOAc–PE) to give a white solid; yield:
1.1609 g (38%); mp 144–145 °C; Rf = 0.34 (EtOAc–PE, 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.5 Hz, 2 H, Harom),
7.34 (t, J = 7.0 Hz, 1 H, Harom), 7.24 (t, J = 7.5 Hz, 2 H, Harom), 7.18
(d, J = 7.0 Hz, 1 H, Harom), 7.16 (t, J = 7.5 Hz, 1 H, Harom), 7.10 (t,
J = 7.0 Hz, 1 H, Harom), 6.98 (d, J = 7.5 Hz, 1 H, Harom), 5.29 (s, 1 H,
CH), 3.02–2.75 (m, 2 H, CH2), 2.43 (t, J = 6.5 Hz, 2 H, CH2), 2.25
(s, 3 H, CH3), 2.14–2.02 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 199.2, 170.7, 163.7, 140.2, 135.3,
135.2, 131.7, 131.4, 129.4, 128.7, 128.6, 128.1, 127.3, 119.3, 37.2,
29.8, 23.1, 17.9.
LRMS (ESI): m/z [2 M + Na]+ calcd for C46H50N2NaO4: 717.4;
found: 717.7.
3-Hydroxyphenanthridin-6(5H)-ones 2a–p and 3q; General
Procedure
N-(3-Oxocyclohex-1-enyl)benzamides 1a–q (0.3 mmol), Cu(OAc)2
(0.1200 g, 0.66 mmol), and Cs2CO3 (0.1960g, 0.6 mmol) were add-
ed to DMA (3.0 mL). The mixture was stirred in a preheated oil-
bath at 130 °C under air (TLC monitoring). After the consumption
of the substrate, the resulting suspension was filtered through a
short pad of celite and the solid material was washed with CH2Cl2–
MeOH (10 mL). The filtrate was concentrated under reduced pres-
sure and the residue was purified by column chromatography (silica
gel) to afford the desired products 2a–p and 3q.
LRMS (ESI): m/z [2 M + Na]+ calcd for C40H38N2NaO4: 633.3;
found: 633.3.
N-(3-Oxocyclohex-1-enyl)-N-phenylbenzamide (1n)
Following the literature procedure,9c 1n was purified by chromatog-
raphy (silica gel, 15% EtOAc–PE) to give a white solid; yield:
1.2231 g (42%); mp 86–88 °C; Rf = 0.39 (EtOAc–PE, 30:70).
5-(2,6-Dimethylphenyl)-3-hydroxyphenanthridin-6(5H)-one
(2a)
Following the general procedure, 2a was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0757
g (80%); mp >300 °C; Rf = 0.39 (EtOAc–PE, 40:60).
1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 7.0 Hz, 2 H, Harom),
7.35–7.18 (m, 6 H, Harom), 7.08 (d, J = 7.5 Hz, 2 H, Harom), 5.44 (s,
1 H, CH), 2.83 (t, J = 6.0 Hz, 2 H, CH2), 2.42 (t, J = 6.5 Hz, 2 H,
CH2), 2.10–2.04 (m, 2 H, CH2).
1H NMR (400 MHz, DMSO-d6): δ = 9.95 (s, 1 H, OH), 8.44 (d, J =
8.0 Hz, 1 H, Harom), 8.37 (d, J = 9.0 Hz, 1 H, Harom), 8.31 (d, J = 8.0
Hz, 1 H, Harom), 7.86 (t, J = 7.5 Hz, 1 H, Harom), 7.57 (t, J = 7.5 Hz,
1 H, Harom), 7.40–7.33 (m, 3 H, Harom), 6.79 (d, J = 8.5 Hz, 1 H,
Harom), 5.90 (s, 1 H, Harom), 1.90 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 199.2, 170.8, 164.4, 141.6, 135.2,
131.4, 129.7, 129.2, 128.3, 128.2, 127.8, 120.8, 37.1, 29.8, 22.9.
LRMS (ESI): m/z [2 M + Na]+ calcd for C38H34N2NaO4: 605.2;
found: 605.4.
13C NMR (100 MHz, DMSO-d6): δ = 160.3, 159.7, 139.0, 136.6,
136.1, 134.9, 133.7, 129.3, 129.1, 128.6, 127.1, 126.0, 124.0, 122.3,
112.2, 111.1, 100.9, 17.6.
N-Benzyl-N-(3-oxocyclohex-1-enyl)benzamide (1o)
Following the literature procedure,15 1o was purified by chromatog-
raphy (silica gel, 20% EtOAc–PE) to give a white solid; yield:
0.5498 g (36%); mp 124–126 °C; Rf = 0.43 (EtOAc–PE, 50:50).
Synthesis 2012, 44, 2374–2384
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 3-Hydroxyphenanthridinone Derivatives
2381
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H34N2NaO4: 653.2;
found: 653.4.
5-(2,6-Dimethylphenyl)-3-hydroxy-9-(trifluoromethyl)phenan-
thridin-6(5H)-one (2f)
Following the general procedure, 2f was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0828
g (72%); mp 247–249 °C; Rf = 0.36 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 10.16 (s, 1 H, OH), 8.81 (s, 1
H, Harom), 8.57 (d, J = 9.0 Hz, 1 H, Harom), 8.50 (d, J = 8.5 Hz, 1 H,
5-(2,6-Dimethylphenyl)-3-hydroxy-9-methylphenanthridin-
6(5H)-one (2b)
Following the general procedure, 2b was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0702
g (71%); mp >300 °C; Rf = 0.38 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 9.93 (s, 1 H, OH), 8.34 (d, J =
9.0 Hz, 1 H, Harom), 8.26 (s, 1 H, Harom), 8.21 (d, J = 8.0 Hz, 1 H,
Harom), 7.40–7.33 (m, 4 H, Harom), 6.79 (d, J = 8.5 Hz, 1 H, Harom),
5.90 (s, 1 H, Harom), 2.52 (s, 3 H, CH3), 1.90 (s, 6 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 160.3, 159.6, 143.9, 139.2,
136.7, 136.1, 134.9, 129.3, 129.0, 128.6, 128.4, 125.9, 122.1, 121.8,
112.1, 111.1, 101.0, 22.1, 17.6.
H
arom), 7.86 (d, J = 8.5 Hz, 1 H, Harom), 7.42–7.35 (m, 3 H, Harom),
6.82 (dd, J = 9.0, 2.0 Hz, 1 H, Harom), 5.92 (d, J = 2.0 Hz, 1 H, Harom),
1.91 (s, 6 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 160.6, 159.5, 139.5, 136.3,
136.0, 135.5, 133.7 (JC-F = 32.0 Hz), 130.2, 129.4, 129.3, 126.8,
126.5, 124.4 (JC-F = 274.0 Hz), 122.9 (JC-F = 3.0 Hz), 119.8 (JC-F
=
4.0 Hz), 112.6, 110.3, 101.1, 17.5.
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H32F6N2NaO4: 789.2;
found: 789.5.
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H38N2NaO4: 681.3;
found: 681.2.
5-(2,6-Dimethylphenyl)-3-hydroxy-7-methylphenanthridin-
6(5H)-one (2g)
Following the general procedure, 2g was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0514
g (52%); mp 295–297 °C; Rf = 0.37 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 9.92 (s, 1 H, OH), 8.32 (d, J =
8.0 Hz, 1 H, Harom), 8.30 (d, J = 7.0 Hz, 1 H, Harom), 7.68 (t, J = 8.0
Hz, 1 H, Harom), 7.38–7.34 (m, 4 H, Harom), 6.75 (dd, J = 9.0, 2.0 Hz,
1 H, Harom), 5.83 (d, J = 2.0 Hz, 1 H, Harom), 2.80 (s, 3 H, CH3), 1.92
(s, 6 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 161.1, 159.6, 142.1, 139.1,
137.1, 136.4, 136.1, 132.7, 130.6, 129.3, 128.9, 126.3, 122.4, 120.5,
112.0, 111.3, 100.4, 24.5, 17.6.
5-(2,6-Dimethylphenyl)-3-hydroxy-9-methoxyphenanthridin-
6(5H)-one (2c)
Following the general procedure, 2c was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0694
g (67%); mp 297–299 °C; Rf = 0.34 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 9.95 (s, 1 H, OH), 8.40 (d, J =
9.0 Hz, 1 H, Harom), 8.24 (d, J = 9.0 Hz, 1 H, Harom), 7.84 (d, J = 1.5
Hz, 1 H, Harom), 7.39–7.32 (m, 3 H, Harom), 7.14 (dd, J = 9.0, 2.0 Hz,
1 H, Harom), 6.78 (dd, J = 8.5, 2.0 Hz, 1 H, Harom), 5.89 (d, J = 2.0
Hz, 1 H, Harom), 4.00 (s, 3 H, OCH3), 1.91 (s, 6 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 163.7, 160.1, 159.8, 139.5,
137.0, 136.8, 136.2, 130.7, 129.3, 129.0, 126.4, 117.6, 115.7, 111.9,
111.1, 104.6, 100.9, 56.3, 17.6.
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H38N2NaO4: 681.3;
found: 681.2.
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H38N2NaO6: 713.3;
found: 713.2.
8-Chloro-5-(2,6-dimethylphenyl)-3-hydroxyphenanthridin-
6(5H)-one (2h) and 10-Chloro-5-(2,6-dimethylphenyl)-3-hy-
droxyphenanthridin-6(5H)-one (2h′)
Following the general procedure, 2h and 2h′ were purified by chro-
matography (silica gel, 20% EtOAc–PE) to give a white solid;
yield: 0.0693 g (66%, 2h/2h′ 56:44); Rf = 0.35 (EtOAc–PE, 40:60).
5-(2,6-Dimethylphenyl)-9-fluoro-3-hydroxyphenanthridin-
6(5H)-one (2d)
Following the general procedure, 2d was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a pale yellow solid; yield:
0.0780 g (78%); mp >300 °C; Rf = 0.36 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 10.09 (s, 1 H, OH), 8.38–8.34
(m, 2 H, Harom), 8.27 (dd, J = 11.0, 2.0 Hz, 1 H, Harom), 7.41–7.33
(m, 4 H, Harom), 6.78 (dd, J = 8.5, 2.0 Hz, 1 H, Harom), 5.89 (d, J =
2.0 Hz, 1 H, Harom), 1.90 (s, 6 H, CH3).
1H NMR (400 MHz, DMSO-d6): δ (major isomer 2h) = 10.06 (s, 1
H, OH), 8.49 (d, J = 9.0 Hz, 1 H, Harom), 8.37 (d, J = 9.0 Hz, 1 H,
Harom), 8.24 (d, J = 2.0 Hz, 1 H, Harom), 7.89 (dd, J = 8.5, 2.0 Hz, 1
H, Harom), 7.41–7.34 (m, 3 H, Harom)*, 6.81 (dd, J = 8.5, 2.0 Hz, 1 H,
13C NMR (100 MHz, DMSO-d6): δ = 166.0 (JC-F = 250.0 Hz), 160.4,
H
arom)*, 5.91 (d, J = 2.0 Hz, 1 H, Harom), 1.90 (s, 6 H, CH3)*; δ (mi-
nor isomer 2h′) = 10.18 (s, 1 H, OH), 9.31 (d, J = 9.0 Hz, 1 H,
Harom), 8.43 (d, J = 7.5 Hz, 1 H, Harom), 8.00 (d, J = 7.5 Hz, 1 H,
159.7, 139.6, 137.8 (JC-F = 10.0 Hz), 136. 4, 136.1, 132.1 (JC-F
=
10.0 Hz), 129.4, 129.2, 126.7, 120.8, 115.3 (JC-F = 24.0 Hz), 112.3,
110.6 (JC-F = 3.0 Hz), 108.2 (JC-F = 24.0 Hz), 101.0, 17.5.
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H32F2N2NaO4: 689.2;
Harom), 7.57 (t, J = 8.0 Hz, 1 H, Harom), 7.41–7.34 (m, 3 H, Harom)*,
6.81 (dd, J = 9.0, 2.0 Hz, 1 H, Harom)*, 5.97 (d, J = 2.0 Hz, 1 H,
Harom), 1.91 (s, 6 H, CH3)*. * Peaks of 2 isomers overlapped.
found: 689.3.
13C NMR (100 MHz, DMSO-d6): δ = 160.2, 159.8, 159.4, 159.3,
139.7, 139.0, 137.4, 136.5, 136.4, 136.0, 135.9, 133.7, 133.6, 131.8,
131.5, 129.5, 129.4, 129.3, 129.2, 129.1, 128.6, 127.6, 127.5, 127.3,
126.2, 125.3, 124.8, 112.6, 111.4, 110.5, 110.0, 101.2, 101.1, 17.6,
17.5 (1 C peak was missing due to overlapping).
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H3235Cl2N2NaO4: 721.2;
found: 721.3 and 721.4.
9-Chloro-5-(2,6-dimethylphenyl)-3-hydroxyphenanthridin-6
(5H)-one (2e)
Following the general procedure, 2e was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a pale yellow solid; yield:
0.0787 g (75%); mp >300 °C; Rf = 0.37 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 10.09 (s, 1 H, OH), 8.54 (s, 1
H, Harom), 8.42 (d, J = 9.0 Hz, 1 H, Harom), 8.29 (d, J = 8.5 Hz, 1 H,
5-(2,6-Dimethylphenyl)-3-hydroxy-8-methoxyphenanthridin-
6(5H)-one (2i) and 5-(2,6-Dimethylphenyl)-3-hydroxy-10-
methoxyphenanthridin-6(5H)-one (2i′)
Following the general procedure, 2i and 2i′ were purified by chro-
matography (silica gel, 20% EtOAc–PE) to give a white solid;
yield: 0.0653 g (63%, 2i/2i′ 53:47); Rf = 0.33 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ (major isomer 2i) = 9.86 (s, 1 H,
OH)*, 8.27 (d, J = 8.5 Hz, 1 H, Harom), 7.77 (d, J = 2.5 Hz, 1 H,
Harom), 7.47 (dd, J = 8.5, 2.0 Hz, 1 H, Harom), 7.40–7.35 (m, 3 H,
H
arom), 7.58 (dd, J = 8.5, 1.5 Hz, 1 H, Harom), 7.40–7.33 (m, 3 H,
Harom), 6.78 (dd, J = 9.0, 2.0 Hz, 1 H, Harom), 5.89 (d, J = 2.0 Hz, 1
H, Harom), 1.90 (s, 6 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 160.4, 159.7, 139.5, 139.2,
136.7, 136.4, 136.0, 130.9, 129.4, 129.2, 127.3, 126.7, 122.5, 122.0,
112.5, 110.1, 100.9, 17.5.
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H3235Cl2N2NaO4: 721.2;
found: 721.4.
Harom)*, 6.79 (d, J = 8.5 Hz, 2 H, Harom), 5.91 (s, 1 H, Harom), 3.91 (s,
© Georg Thieme Verlag Stuttgart · New York
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2382
Q. Yu et al.
PAPER
3 H, OCH3), 1.91 (s, 6 H, CH3)*; δ (minor isomer 2i′) = 9.93 (s, 1
H, OH)*, 9.14 (d, J = 9.0 Hz, 1 H, Harom), 8.38 (d, J = 9.0 Hz, 1 H,
1 H, Harom), 7.33 (m, 1 H, Harom), 7.25 (d, J = 8.0 Hz, 1 H, Harom),
7.13 (d, J = 8.0 Hz, 1 H, Harom), 6.76 (d, J = 8.5 Hz, 1 H, Harom), 5.95
(s, 1 H, Harom), 2.41 (s, 3 H, CH3), 1.90 (s, 3 H, CH3).
Harom), 8.05 (t, J = 5.0 Hz, 1 H, Harom), 7.54 (d, J = 5.0 Hz, 2 H,
H
arom), 7.40–7.35 (m, 3 H, Harom)*, 5.97 (s, 1 H, Harom), 4.09 (s, 3 H,
13C NMR (100 MHz, DMSO-d6): δ = 160.9, 159.4, 140.2, 138.7,
135.9, 135.1, 134.8, 133.5, 132.3, 129.3, 128.7, 128.5, 127.1, 125.7,
124.1, 122.2, 112.0, 111.0, 102.1, 21.2, 17.3.
LRMS (ESI): m/z [2 M + Na]+ calcd for C42H34N2NaO4: 653.2;
found: 653.5.
OCH3), 1.91 (s, 6 H, CH3)*. * Peaks of two isomers overlapped.
13C NMR (100 MHz, DMSO-d6): δ = 160.1, 160.0, 158.8, 158.7,
158.6, 157.1, 138.9, 137.9, 136.9, 136.8, 136.0, 135.9, 130.9, 129.3,
129.0, 128.5, 127.4, 126.1, 125.2, 124.2, 124.1, 122.8, 120.8, 116.1,
112.2, 111.5, 111.3, 110.9, 109.5, 101.0, 100.8, 56.7, 55.9, 17.5
(four carbon peaks were missing due to overlapping).
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H38N2NaO6: 713.3;
found: 713.3 and 713.4.
3-Hydroxy-5-(o-tolyl)phenanthridin-6(5H)-one (2m)
Following the general procedure, 2m was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a pale yellow solid; yield:
0.0389 g (43%); mp 271–273 °C; Rf = 0.37 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 9.94 (s, 1 H, OH), 8.43 (d, J =
8.0 Hz, 1 H, Harom), 8.34 (d, J = 8.5 Hz, 1 H, Harom), 8.30 (d, J = 8.0
Hz, 1 H, Harom), 7.85 (t, J = 7.5 Hz, 1 H, Harom), 7.58–7.44 (m, 4 H,
Harom), 7.27 (d, J = 7.0 Hz, 1 H, Harom), 6.78 (dd, J = 8.5, 2.0 Hz, 1
H, Harom), 5.92 (d, J = 2.0 Hz, 1 H, Harom), 1.96 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 160.8, 159.4, 140.1, 137.8,
136.4, 134.9, 133.6, 131.8, 129.6, 129.4, 128.5, 128.2, 127.1, 125.8,
124.1, 122.2, 112.0, 111.0, 102.1, 17.3.
5-(2,6-Dimethylphenyl)-3-hydroxy-8-(trifluoromethyl)phenan-
thridin-6(5H)-one (2j)
Following the general procedure, 2j was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0817
g (71%); mp 296–297 °C; Rf = 0.36 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 10.23 (s, 1 H, OH), 8.69 (d, J =
8.5 Hz, 1 H, Harom), 8.56 (s, 1 H, Harom), 8.47 (d, J = 9.0 Hz, 1 H,
Harom), 8.16 (d, J = 8.5 Hz, 1 H, Harom), 7.43–7.36 (m, 3 H, Harom),
6.85 (dd, J = 8.5, 2.0 Hz, 1 H, Harom), 5.94 (d, J = 2.0 Hz, 1 H, Harom),
1.92 (s, 6 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 161.0, 159.6, 139.9, 138.2,
136.2, 136.0, 129.5 (JC-F = 4.0 Hz), 129.4, 129.3, 127.2 (JC-F = 32.0
Hz), 127.0, 125.6 (JC-F = 4.0 Hz), 124.5 (JC-F = 271.0 Hz), 124.0,
123.8, 112.8, 110.1, 101.1, 17.5.
LRMS (ESI): m/z [2 M + Na]+ calcd for C40H30N2NaO4: 625.2;
found: 625.5.
3-Hydroxy-5-phenylphenanthridin-6(5H)-one (2n)
Following the general procedure, 2n was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0259
g (30%); mp >300 °C; Rf = 0.38 (EtOAc–PE, 40:60).
LRMS (ESI): m/z [2 M + Na]+ calcd for C44H32F6N2NaO4: 789.2;
1H NMR (400 MHz, DMSO-d6): δ = 9.96 (s, 1 H, OH), 8.41 (d, J =
8.0 Hz, 1 H, Harom), 8.33 (d, J = 9.0 Hz, 1 H, Harom), 8.29 (d, J = 7.5
Hz, 1 H, Harom), 7.83 (t, J = 7.5 Hz, 1 H, Harom), 7.66 (t, J = 7.5 Hz,
2 H, Harom), 7.59 (d, J = 7.5 Hz, 1 H, Harom), 7.55 (d, J = 7.5 Hz, 1
H, Harom), 7.38 (d, J = 7.5 Hz, 2 H, Harom), 6.77 (dd, J = 8.5, 2.0 Hz,
1 H, Harom), 6.00 (d, J = 2.0 Hz, 1 H, Harom).
13C NMR (100 MHz, DMSO-d6): δ = 161.3, 159.1, 140.9, 138.9,
134.8, 133.5, 130.5, 129.7, 129.1, 128.5, 127.1, 125.6, 124.2, 122.2,
111.9, 111.0, 102.9.
found: 789.3.
5-(2,6-Dimethylphenyl)-3-hydroxy-8,9-dimethoxyphenanthri-
din-6(5H)-one (2k)
Following the general procedure, 2k was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0710
g (63%); mp 286–288 °C; Rf = 0.31 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 9.82 (s, 1 H, OH), 8.37 (d, J =
8.5 Hz, 1 H, Harom), 7.84 (s, 1 H, Harom), 7.71 (s, 1 H, Harom), 7.39–
7.33 (m, 3 H, Harom), 8.76 (d, J = 8.5, 1.5 Hz, 1 H, Harom), 5.88 (d,
J = 1.0 Hz, 1 H, Harom), 4.05 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3),
1.89 (s, 6 H, CH3).
LRMS (ESI): m/z [2 M + Na]+ calcd for C38H26N2NaO4: 597.2;
found: 597.2.
13C NMR (100 MHz, DMSO-d6): δ = 159.9, 158.9, 154.3, 149.1,
138.5, 136.9, 136.1, 129.9, 129.3, 129.0, 125.8, 117.4, 111.9, 111.3,
108.8, 103.9, 100.8, 56.6, 16.0, 17.6.
5-Benzyl-3-hydroxyphenanthridin-6(5H)-one (2o)
Following the general procedure, 2o was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0217
g (24%); mp 265–267 °C; Rf = 0.35 (EtOAc–PE, 40:60).
LRMS (ESI): m/z [2 M + Na]+ calcd for C46H42N2NaO8: 773.3;
1H NMR (400 MHz, DMSO-d6): δ = 10.06 (s, 1 H, OH), 8.39 (t, J =
8.5 Hz, 2 H, Harom), 8.32 (d, J = 8.5 Hz, 1 H, Harom), 7.82 (t, J = 7.5
Hz, 1 H, Harom), 7.56 (t, J = 7.5 Hz, 1 H, Harom), 7.33 (t, J = 7.0 Hz,
1 H, Harom), 7.32 (d, J = 7.5 Hz, 1 H, Harom), 7.25 (d, J = 7.5 Hz, 1
H, Harom), 7.23 (d, J = 7.5 Hz, 2 H, Harom), 6.77 (d, J = 9.0 Hz, 1 H,
found: 773.5.
5-(2,6-Dimethylphenyl)-3-hydroxy-9,10-dimethoxyphenanthri-
din-6(5H)-one (2k′)
Following the general procedure, 2k′ was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0079
g (7%); mp 283–285 °C; Rf = 0.32 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 10.00 (br s, 1 H, OH), 9.02 (d,
J = 9.0 Hz, 1 H, Harom), 8.18 (d, J = 8.5 Hz, 1 H, Harom), 7.38–7.31
(m, 4 H, Harom), 6.77 (d, J = 9.0 Hz, 1 H Harom), 5.89 (s, 1 H, Harom),
3.99 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 1.89 (s, 6 H, CH3).
Harom), 6.75 (s, 1 H, Harom), 5.55 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 161.7, 159.5, 138.9, 137.3,
134.5, 133.4, 129.1, 128.7, 127.5, 127.1, 126.8, 125.8, 123.6, 122.1,
111.7, 111.3, 102.5, 45.9.
LRMS (ESI): m/z [2 M – H]– calcd for C40H29N2O4: 601.2; found:
LRMS (ESI): m/z [2 M + Na]+ calcd for C46H42N2NaO8: 773.3;
601.5.
found: 773.5.
3-Hydroxyphenanthridin-6(5H)-one (2p)
Following the general procedure, 2p was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a white solid; yield: 0.0095
g (15%); mp 151–153 °C; Rf = 0.39 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 9.57 (s, 1 H, OH), 8.17 (s, 1 H,
NH), 8.16 (d, J = 7.5 Hz, 1 H, Harom), 7.62–7.57 (m, 4 H, Harom), 7.11
(d, J = 2.0 Hz, 1 H, Harom), 6.87 (dd, J = 8.5, 2.0 Hz, 1 H, Harom).
5-(2,4-Dimethylphenyl)-3-hydroxyphenanthridin-6(5H)-one
(2l)
Following the general procedure, 2l was purified by chromatogra-
phy (silica gel, 20% EtOAc–PE) to give a pale yellow solid; yield:
0.0426 g (45%); mp 281–283 °C; Rf = 0.38 (EtOAc–PE, 40:60).
1H NMR (400 MHz, DMSO-d6): δ = 9.93 (s, 1 H, OH), 8.42 (d, J =
8.0 Hz, 1 H, Harom), 8.34 (d, J = 9.0 Hz, 1 H, Harom), 8.29 (d, J = 8.0
Hz, 1 H, Harom), 7.84 (t, J = 7.5 Hz, 1 H, Harom), 7.56 (t, J = 7.5 Hz,
13C NMR (100 MHz, DMSO-d6): δ =163.1, 155.5, 144.4, 142.9,
133.3, 132.2, 129.7, 129.0, 127.5, 127.1, 114.3, 111.3, 105.2.
Synthesis 2012, 44, 2374–2384
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of 3-Hydroxyphenanthridinone Derivatives
2383
LRMS (ESI): m/z [M – H]– calcd for C13H8NO2: 210.1; found:
210.5.
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N-(3-Hydroxyphenyl)benzamide (2p′)16
Following the general procedure, 2p′ was purified by chromatogra-
phy (silica gel, 30% EtOAc–PE) to give a white solid; yield: 0.0128
g (20%); mp 165–167 °C; Rf = 0.35 (EtOAc–PE, 60:40).
1H NMR (400 MHz, DMSO-d6): δ = 10.13 (s, 1 H, OH), 9.42 (s, 1
H, NH), 7.94 (d, J = 7.5 Hz, 2 H, Harom), 7.59 (t, J = 7.0 Hz, 1 H,
Harom), 7.53 (d, J = 7.5 Hz, 1 H, Harom), 7.52 (t, J = 7.0 Hz, 1 H,
Harom), 7.38 (s, 1 H, Harom), 7.18 (d, J = 8.0 Hz, 1 H, Harom), 7.12 (t,
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J = 8.0 Hz, 1 H, Harom), 6.52 (d, J = 7.5 Hz, 1 H, Harom).
LRMS (ESI): m/z [2 M + Na]+ calcd for C26H22N2NaO4 449.1;
found: 449.5.
5-(2,6-Dimethylphenyl)-1,1-dimethyl-1,10b-dihydrophenan-
thridine-3,6(2H,5H)-dione (3q)
Following the general procedure, 3q was purified by silica gel chro-
matography (15% EtOAc–PE) yellow solid; yield: 0.0435 g (42%);
mp 203–205 °C; Rf = 0.36 (EtOAc–PE, 30:70).
1H NMR (400 MHz, CDCl3): δ = 8.58 (d, J = 8.5 Hz, 1 H, Harom),
7.79–7.75 (m, 2 H, Harom), 7.51 (t, J = 7.0 Hz, 1 H, Harom), 7.26 (t,
J = 8.0 Hz, 1 H, Harom), 7.15 (d, J = 7.5 Hz, 2 H, Harom), 6.63 (s, 1 H,
CH), 2.10 (s, 6 H, CH3), 1.88 (s, 1 H, CH), 1.87 (s, 2 H, CH2), 1.58
(s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 161.9, 151.2, 139.8, 138.9, 137.5,
136.6, 133.7, 132.5, 130.1, 129.2, 128.5, 125.6, 125.0, 122.3, 48.9,
29.7, 29.6, 23.0, 18.0.
LRMS (ESI): m/z [M + H]+ calcd for C23H24NO2: 346.2; found:
346.3.
Acknowledgment
We acknowledge the National Natural Science Foundation of China
(#21072148) and Cultivation Foundation (B) for Young Faculty of
Tianjin University (TJU-YFF-08B68) for financial support.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
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nfomartit
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© Georg Thieme Verlag Stuttgart · New York
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prepare such compounds under various condensation
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(11) We thank one reviewer for suggesting such non-metallic
hypervalent iodine oxidants for this cross-coupling and
dehydrogenative reaction..
conditions were not successful.
(13) For the previous examples describing such C(sp2)–C(sp2)
bond coupling mediated by Pd, see refs. 2c, 6a, and 6h.
(14) For a previous example involving the Cu(II)-mediated SET
process, see ref. 4c.
(15) Ninomiya, B. I.; Naito, T.; Kiguchi, T. J. Chem. Soc., Perkin
Trans. 1 1973, 2257.
(12) In order to further study the substrate scope, we also
managed to prepare the substrates containing the bulky
isopropyl and tert-butyl groups. However, attempts to
(16) (a) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272.
(b) Faler, C. A.; Joullié, M. M. Tetrahedron Lett. 2006, 47,
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© Georg Thieme Verlag Stuttgart · New York