Synthesis of 6-Substituted Phenanthridine Derivatives by Palladium-Catalysed Domino Suzuki-Miyaura/Aza-Michael Reactions

Article abstract of DOI:10.1002/ejoc.201402913

An efficient method for the synthesis of 6-substituted phenanthridine derivatives has been developed through a one-pot process involving a sequence of palladium-catalysed Suzuki-Miyaura reaction followed by intramolecular aza-Michael addition. This method is applicable to the synthesis of a wide range of substituted phenanthridines from simple substrates.

Full text of DOI:10.1002/ejoc.201402913

Job/Unit: O42913
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Date: 07-10-14 16:41:29
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201402913
Synthesis of 6-Substituted Phenanthridine Derivatives by Palladium-Catalysed
Domino Suzuki–Miyaura/Aza-Michael Reactions
Xiaobo Bao,[a] Wei Yao,[b] Qihua Zhu,*[a] and Yungen Xu*[a,b]
Keywords: Homogeneous catalysis / Palladium / Domino reactions / Cyclization / Nitrogen heterocycles
An efficient method for the synthesis of 6-substituted phen-
anthridine derivatives has been developed through a one-pot
Miyaura reaction followed by intramolecular aza-Michael
addition. This method is applicable to the synthesis of a wide
process involving a sequence of palladium-catalysed Suzuki– range of substituted phenanthridines from simple substrates.
Tandem reactions involving metal catalysis are one of the
Introduction
most efficient methods to rapidlysynthesize target mol-
Phenanthridine derivatives are the frameworks of many ecules from easily accessible starting materials.[14,15] Our
natural products and biologically active compounds.[1,2] previous work has established a new strategy for the synthe-
Some 5,6-secolycorines, with a 5,6-dihydrophenanthridine sis of O-heterocycles using a tandem reaction. In this way,
skeleton, have been reported to act as potent inhibitors of it was easy to construct benzo[c]chromenes by a sequential
acetylcholinesterase (AChE),[3] and a series of phenanthrid- Suzuki–Miyaura reaction and intramolecular Michael ad-
inyl acetamides have been synthesized and evaluated as dition.[16] As a result of our research into general and ef-
bradykinin B1 receptor antagonists, which are potentially ficient methods to synthesize N-heterocycles, in this paper,
useful in the prevention of inflammation.[4] To discover we report a palladium-catalysed Suzuki–Miyaura reaction
more biologically active compounds, a facile and high- coupled with an aza-Michael addition to synthesize 6-sub-
yielding route to construct the 6-substituted phenanthridine stituted-phenanthridine derivatives.
framework is required.
In contrast to the well-developed syntheses of phen-
anthridines, only a few methods for preparation of 5,6-di-
hydrophenanthridines have been reported.[5–9] The main
strategy for the synthesis of the target molecules has fo-
cussed on C–H activation, and pioneering works were re-
ported to produce 5-(phenylsulfonyl)-5,6-dihydrophen-
anthridine-6-acetate derivatives.[10–12] Another method that
has been used for the synthesis of these molecules is a modi-
fied Pictet–Spengler reaction, mediated by the peptide-cou-
pling agent propylphosphonic anhydride (T3P).[13] How-
ever, these literature methods are limited in selectivity, yield,
or substrate scope, or they had to use special additives. To
the best of our knowledge, there are few methods that could
be used to prepare various 5,6-dihydrophenanthridine-6-
acetate derivatives efficiently under simple and mild condi-
tions in excellent yields in one pot.
Results and Discussion
In the above-mentioned reaction, β-(2-boronate)phenyl-
substituted α,β-unsaturated compounds were coupled with
2-bromoanilines to form an aryl C–C bond by a Suzuki–
Miyaura reaction, and a C–N bond by an intramolecular
aza-Michael addition (Table 1). It is noteworthy that when
R1 was COOEt, COOMe, or CN (Table 1, entries 1–6), we
obtained compounds 3 as the products in moderate to good
yield. When α,β-unsaturated ketones (Table 1, entries 7–12)
were used as the carbonyl substrates, only the C–C cleavage
products, i.e., the phenanthridines, were obtained. LC–MS
analysis indicated that acetophenone and phenanthridine
were the major products of the reaction reported in Table 1,
entry 10. Previous workers have mentioned the cleavage of
C–C bonds, and explained it as a retro-Mannich reac-
tion.[17,18] We propose a possible mechanism for this retro-
Mannich reaction such that 6-(2-oxopropyl)- or 6-benzo-
ylmethyl-5,6-dihydrophenanthridines, which are Mannich
bases, can easily undergo removal of the ketone group by
proton transfer under the basic conditions. Therefore, we
assumed that the presence of the N–H group plays a key
role in the rearrangement process to form phenanthridines
4 (Scheme 1).
[a] Jiangsu Key Laboratory of Drug Design and Optimization, and
Department of Medicinal Chemistry, China Pharmaceutical
University,
Nanjing 21009, China
E-mail: xu_yungen@hotmail.com
http://yxy.cpu.edu.cn/
[b] Department of Medicinal Chemistry, China Pharmaceutical
University,
Nanjing 21009, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402913.
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X. Bao, W. Yao, Q. Zhu, Y. Xu
FULL PAPER
Table 1. Scope of the reaction with respect to 2-bromoanilines; which is why the retro-Mannich reaction occurred. 6-Tosyl-
DME = 1,2-dimethoxyethane.[a,b]
5,6-dihydrophenanthridine 6a was obtained smoothly in
high yield when p-tolylsulfonyl was used as the N-protecting
Table 2. Optimization of the protecting group.[a,b]
Entry
R1
R2
Yield of 3 [%][c] Yield of 4 [%][c]
1
2
3
4
5
6
7
8
COOEt
COOEt
COOEt
COOMe
COOMe
CN
COMe
COMe
COMe
COPh
COPh
COPh
COOEt
COPh
H
Me
F
H
F
H
H
F
Me
H
85, 3a
–
–
–
–
–
–
85, 3b
75, 3c
72, 3d
Entry
R
Yield of 6 [%][c]
Yield of 4 [%][c]
67, 3e
63, 3f
1
2
3
Ts
Tf
Ac
85, 6a
–
–
–
–
–
–
–
–
–
–
–
65, 4a
71, 4b
69, 4c
82, 4a
75, 4b
70, 4c
51, 4a
64, 4a
66, 4a
70, 4a
9
[a] Tf = trifluoroacetyl, Ts = p-tolylsulfonyl, Ac = acetyl. [b] All
reactions were carried out using 1a (1 mmol) and 5 (1 mmol) in
DME with Na2CO3 (2 m aq.; 6 mmol) and Pd(PPh3)4 (0.1 mmol)
under N2 at reflux for 4 h. [c] Isolated yield.
10
11
12
13[d]
14[e]
F
Me
H
H
[a] pin = pinacolyl. [b] All reactions were carried out using 1
(1 mmol) and 2 (1 mmol) in DME with Na2CO3 (2 m aq.; 6 mmol)
and Pd(PPh3)4 (0.1 mmol) under N2 at reflux for 4 h. [c] Isolated
yield. [d] This reaction was carried out in DMF at 140 °C for 8 h.
[e] This reaction was carried out at 0 °C for 4 h, and then room
temperature for 4 h.
Table 3. Optimization of the reaction conditions; dppf = 1,1Ј-
bis(diphenylphosphino)ferrocene, dba = dibenzylideneacetone.[a]
Entry Pd source
Base
Solvent
Yield [%][c]
1
2
3
4
5
6
7
8
Pd(dppf)Cl2·CH2Cl2 K2CO3 (2 m)
DME
DME
DME
DME
DME
74
79
23
46
62
23
41
47
51
26
trace
27
85
35
34
25
20
–
Pd(PPh3)4
Pd(dba)2
K2CO3 (2 m)
K2CO3 (2 m)
K2CO3 (2 m)
K2CO3 (2 m)
K2CO3 (2 m)
K2CO3 (2 m)
DIPEA
Pd(dppf)Cl2
Pd(PPh3)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
–
DMF[b]
1,4-dioxane
DME
9
DBU
DME
DME
DME
DME
10
11
12
13
14
15
16
17
18
piperazine
pyrrolidine
TMEDA
Scheme 1. Possible mechanism of the reaction and decomposition.
Na2CO3 (2 m)
Na2CO3 (2 m)
CsF
DME
DME[d]
DME
In order to avoid the occurrence of the retro-Mannich
reaction, our first challenge was to find an N-protecting
group. A set of potential protecting groups were examined
in the reactions of 1a with 5 under Pd(PPh3)4 catalysis
(10 mol-%) using Na2CO3 as base in DME at reflux
(Table 2). The results showed that phenanthridine 4 was ob-
tained by retro-Mannich reaction when acetyl or trifluoro-
acetyl was selected as the N-protecting group. These groups
CsF
K3PO4
DMF[b]
DMF[b]
DME
Na2CO3 (2 m)
[a] All reactions were carried out using 1a (1 mmol) and 5a
(1 mmol) in the solvent with base (6 mmol) and catalyst (0.1 mmol)
under N2 at reflux for 4 h. [b] In DMF, the reaction temperature
was 100 °C. [c] Isolated yield. [d] This reaction was carried out at
are not stable under basic high-temperature conditions, 60 °C for 6 h.
2
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Synthesis of 6-Substituted Phenanthridine Derivatives
group The conditions were then optimized conditions by Table 5. Scope of the reaction with respect to N-tosyl-2-ami-
nophenyl boronates.[a]
investigating the reaction between 1a and 5a (Table 3).
First, several Pd sources were investigated (Table 3, en-
tries 1–5). Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2, and Pd(dppf)
Cl2 gave relatively high yields, and of these, Pd(PPh3)4
turned out to have the highest efficiency. Subsequently, a
series of solvents, including DMF, 1,4-dioxane, and DME,
were screened (Table 3, entries 5–7). The results indicated
that DME, which gave better results than DMF and 1,4-
dioxane, was the most suitable solvent for this protocol.
In both the Suzuki and Michael reactions, base undoubt-
edly impacts the yield and procedure, especially in the palla-
dium-catalysed Suzuki–Miyaura reaction in which it plays
multiple roles.[19] Therefore, we tested both organic (Table 3,
entries 8–13) and inorganic (Table 3, entries 2, 14–16) bases
for this protocol. We found that some organic bases gave
moderate yields, such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU; 51%) and N,N-diisopropyl-ethylamine (DIPEA,
47%), which may be due to their strongly basic properties.
For N,N,NЈ,NЈ-tetramethylethane-1,2-diamine (TMEDA),
piperazine, and pyrrolidine, the yields were low, even to the
extent that only traces of products were formed. Compared
to organic bases which gave up to 51% yields, the influence
of inorganic bases on the reaction was complex. CsF and
K3PO4, both common bases for Suzuki cross-coupling, did
not give good yields in either DME or DMF (Table 3, en-
tries 14–16). We were pleased to find that moderate to good
yields could be obtained when the reaction between 1a and
5a was carried out in DME, a water-miscible solvent, with
Na2CO3 (2 m aq.) (Table 3, entry 13) or K2CO3 (2 m aq.)
(Table 3, entry 2). This could be a result of the fact that
Na2CO3 has the right pKa for boron complexation, a pro-
cess that depends on both the pH and the water concentra-
tion in the reaction medium.[20] In addition, we found that
in the absence of palladium, no reaction occurred, not even
an aza-Michael addition (Table 3, entry 18).
Table 4. Scope of the reaction with respect to N-tosyl-2-bromoanil-
ines.[a]
Entry
R1
R2
Yield [%][b]
1
2
3
4
5
6
7
8
COMe
COMe
COMe
COPh
COPh
COPh
COOEt
COOEt
H
Me
F
H
Me
F
85, 6a (9a)
92, 6b
83, 6c
87, 6d
88, 6e
80, 6f
H
Me
90, 6g
82, 6h
[a] All reactions were carried out using 7 (1 mmol) and 8 (1 mmol)
in DME with Na2CO3 (2 m aq.; 6 mmol) and Pd(PPh3)4 (0.1 mmol)
under N2 at reflux for 4 h. [b] Isolated yield.
[a] All reactions were carried out using 1 (1 mmol) and 5 (1 mmol)
in DME with Na2CO3 (2 m aq.; 6 mmol) and Pd(PPh3)4 (0.1 mmol)
under N2 at reflux for 4 h. [b] Isolated yield.
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X. Bao, W. Yao, Q. Zhu, Y. Xu
FULL PAPER
(1H NMR at 300 MHz, 13C NMR at 75 MHz). The chemical shift
data for H NMR spectra were calibrated using residual CHCl3 (δ
Having established the optimal reaction conditions, the
scope of this transformation was investigated by testing the
reaction of N-tosyl-2-bromoanilines with β-(2-boronate)-
phenyl-α,β-unsaturated carbonyl compounds. As shown in
Table 4, all of the combinations tested produced the desired
5,6-dihydrophenanthridines in good to excellent isolated
yields. The R1 group could be a ketone (Table 4, entries 1–
6) or an ester (Table 4, entries 7 and 8), and the position 4
substituent R2 ranged from H and F atom (the latter being
electron-withdrawing) to Me (electron-donating group).
To further extend the scope of the reaction, N-tosyl-2-
aminophenyl boronates were treated with a series of vinyl/
aryl bromides prepared by Wittig reactions, and the results
are summarized in Table 5. We found that the reaction of
vinyl/aryl bromides and aryl boronates proceeded smoothly
and to give the corresponding products 9 in good to excel-
lent yields. For example, using vinyl bromides, under the
optimized conditions, the desired compounds (i.e., 9a–9c,
9h, and 9i) were obtained in good yields (Table 5, entries 1–
3, 8–9). Heteroaryl substrates were also suitable coupling
partners, and gave the corresponding products in satisfac-
tory yields. Electron-withdrawing or electron-donating
groups at C-4 of the benzene ring did not exert a significant
impact on the reactivity (Table 5, entries 13–16). Clearly,
the palladium catalysed tandem intermolecular Suzuki cou-
pling followed by intramolecular Michael addition reaction
in one pot is an easy way to generate a library of com-
pounds 9.
1
= 7.26 ppm). For 13C NMR spectra, the chemical shifts in CDCl3
were calibrated to the CDCl3 resonance (δ = 77.0 ppm). Analytical
TLC was carried out with plates precoated with silica gel F254
(0.25 mm thick). Melting points were measured with an RY-1 melt-
ing point apparatus.
General Procedures for the Synthesis of the 6-Substituted 5,6-Di-
hydrophenanthridines
Procedure a: β-(2-Boronate)phenyl-α,β-unsaturated compounds 1
(1 mmol, 1 equiv.) and 2-bromoanline 2 or 5 (1 mmol, 1 equiv.)
were dissolved in DME (15 mL) in a Schlenk-type flask under N2,
and Na2CO3 (2 m aq.; 6 equiv.) and Pd(PPh3)4 (0.1 mmol,
0.1 equiv.) were added. The resulting mixture was heated at reflux
for 4 h. The mixture was cooled to room temperature, and the solid
was removed by filtration. The filtrate was concentrated under re-
duced pressure. The crude product was immediately purified by
flash chromatography (silica gel 60, particle size 200–300 mesh, pe-
troleum ether/EtOAc, 15:1).
Procedure b: To a Schlenk-type flask containing the vinyl/aryl
bromide 7 (1 mmol, 1 equiv.) and N-tosyl-2-aminophenyl boronate
8 (1 mmol, 1 equiv.) were dissolved in DME (15 mL) under N2, and
Na2CO3 (2 m aq.; 6 equiv.) and Pd(PPh3)4 (0.1 mmol, 0.1 equiv.)
was added. The resulting mixture was heated at reflux for 4 h. The
mixture was cooled to room temperature, and the solid was re-
moved by filtration. The filtrate was concentrated under reduced
pressure. The crude product was immediately purified by flash
chromatography (silica gel 60, particle size 200–300 mesh, petro-
leum ether/EtOAc, 15:1).
Based on the literature,[17,18] and on the results obtained
in this work, we proposed a possible mechanism for the
reaction and decomposition (Scheme 1). The results in
Tables 1, 4, and 5 indicate that only the reactions between
N-unprotected 2-bromoanilines and α,β-unsaturated ketone
carbonyl substrates led to the formation of phenanthridines
4.
Ethyl 2-(5,6-Dihyphenanthridin-6-yl)acetate (3a): Yield 85%. White
solid, m.p. 102–103 °C. H NMR (300 MHz, CDCl3): δ = 7.76 (d,
1
J = 8.0 Hz, 1 H), 7.27 (dd, J = 7.9, 1.26 Hz, 1 H), 7.36 (td, J =
7.6, 1.4 Hz, 1 H), 7.26 (td, J = 7.4, 1.2 Hz, 1 H), 7.19–7.11 (m, 2
H), 6.87 (td, J = 7.7, 1.1 Hz, 1 H), 6.72 (dd, J = 7.9, 0.9 Hz, 1 H),
4.86 (dd, J = 10.3, 3.1 Hz, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 2.88
(dd, J = 16.5, 10.4 Hz, 1 H), 2.45 (dd, J = 16.5, 3.2 Hz, 1 H), 1.27
(t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.69,
142.57, 134.21, 130.66, 128.71, 127.52, 126.86, 125.56, 122.89,
122.20, 120.30, 119.02, 115.73, 60.52, 51.66, 39.50, 13.93 ppm.
Conclusions
Ethyl 2-(5,6-Dihydro-2-methylphenanthridin-6-yl)acetate (3b): Yield
In summary, a new method for the synthesis of 6-substi-
tuted phenanthridine derivatives has been developed
through a one-pot process involving a sequential palladium-
catalysed Suzuki–Miyaura reaction and intramolecular aza-
Michael addition. The scope, limitations, and possible
mechanism of this protocol have been discussed. As a facile
method to produce a variety of 6-substituted phenanthrid-
ine derivatives, this strategy would be useful in organic syn-
thesis and medicinal chemistry.
1
85%. White solid, m.p. 140–143 °C, H NMR (300 MHz, CDCl3):
δ = 7.73 (d, J = 7.7 Hz, 1 H), 7.51 (s, 1 H), 7.33 (td, J = 7.6, 1.4 Hz,
1 H), 7.23 (td, J = 7.3, 1.1 Hz, 1 H), 7.13 (d, J = 6.8 Hz, 1 H), 6.95
(d, J = 7.4 Hz, 1 H), 6.62 (d, J = 8.0 Hz, 1 H), 4.79 (dd, J = 10.3,
3.1 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 2.86 (dd, J = 10.3, 1.47 Hz,
1 H), 2.41 (td, J = 3.2, 16.4 Hz, 1 H), 2.32 (s, 3 H), 1.25 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.94, 139.82,
134.13, 130.79, 129.34, 127.69, 127.42, 126.74, 125.50, 123.20,
122.11, 120.33, 115.49, 60.01, 51.91, 39.32, 20.35, 13.80 ppm.
Ethyl 2-(2-Fluoro-5,6-dihydrophenanthridin-6-yl)acetate (3c): Yield
1
75%. White solid, m.p. 136–138 °C. H NMR (300 MHz, CDCl3):
δ = 7.65 (d, J = 7.7 Hz, 1 H), 7.39 (dd, J = 9.9, 2.8 Hz, 1 H), 7.33
(dd, J = 7.6, 1.3 Hz, 1 H), 7.30–7.23 (m, 1 H), 7.14 (dd, J = 7.4,
0.8 Hz, 1 H), 6.85 (td, J = 8.5, 2.8 Hz, 1 H), 6.63 (dd, J = 8.7,
4.8 Hz, 1 H), 5.19 (br. s, 1 H), 4.80 (dd, J = 10.4, 3.0 Hz, 1 H),
4.17 (q, J = 7.1 Hz, 2 H), 2.83 (dd, J = 16.5, 10.4 Hz, 1 H), 2.41
(dd, J = 16.5, 3.1 Hz, 1 H), 1.26 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 171.84, 158.03, 134.09, 127.57,
127.46, 125.52, 122.30, 116.19, 116.05, 115.39, 115.03, 109.32,
109.05, 60.32, 51.91, 39.41, 13.94 ppm.
Experimental Section
General Methods: All reagents and solvents were either purified
by standard techniques, or used a supplied without any further
purification. LC–MS analysis was carried out using a Waters AC-
QUITY UPLC system, using the ESI-MS technique. HRMS spec-
tra were acquired with a Waters Q-TOF microTM apparatus. Com-
pounds were visualized under a UV lamp (254 nM). NMR spectra
were obtained with a Bruker DPX 300 MHz NMR spectrometer
4
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Synthesis of 6-Substituted Phenanthridine Derivatives
Methyl 2-(5,6-Dihydrophenanthridin-6-yl)acetate (3d): Yield 72%.
Colourless oil. 1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J =
7.7 Hz, 1 H), 7.69 (dd, J = 7.8, 1.1 Hz, 1 H), 7.33 (td, J = 7.6,
1.3 Hz, 1 H), 7.26–7.20 (m, 2 H), 7.15–7.09 (m, 2 H), 6.84 (td, J =
7.5, 0.8 Hz, 1 H), 6.69 (d, J = 7.9 Hz, 1 H), 4.82 (dd, J = 10.4,
3.0 Hz, 1 H), 3.69 (s, 3 H), 2.87 (dd, J = 16.6, 10.4 Hz, 1 H), 2.43
(dd, J = 16.7, 3.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
172.19, 142.33, 133.84, 130.80, 128.71, 127.56, 126.72, 125.56,
122.94, 122.21, 120.43, 118.65, 115.61, 51.67, 51.15, 39.50 ppm.
HRMS (ESI): calcd. for C16H15NO2Na [M + Na]+ 276.1000; found
276.1003.
109.82, 109.51, 54.70, 48.37, 29.31, 20.82 ppm. HRMS (ESI): calcd.
for C23H20NFO3SNa [M + Na]+ 432.1046; found 432.1054.
2-(5,6-Dihydro-5-tosylphenanthridin-6-yl)-1-phenylethanone (6d):
1
Yield 87 %. White solid, m.p. 144–147 °C. H NMR (300 MHz,
CDCl3): δ = 7.76 (d, J = 1.3 Hz, 1 H), 7.73 (d, J = 1.3 Hz, 1 H),
7.65–7.59 (m, 1 H), 7.54–7.43 (m, 2 H), 7.41–7.33 (m, 2 H), 7.30–
7.20 (m, 2 H), 7.30–7.21 (m, 2 H), 7.15–7.04 (m, 2 H), 6.95 (d, J
= 8.3 Hz, 2 H), 6.69 (d, J = 8.1 Hz, 2 H), 6.08 (dd, J = 7.9, 5.9 Hz,
1 H), 3.34 (dd, J = 16.4, 8.1 Hz, 1 H), 3.01 (dd, J = 16.4, 8.1 Hz,
1 H), 2.14 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 195.75,
142.60, 142.37, 136.20, 134.08, 133.73, 132.95, 132.72, 132.12,
129.55, 128.95, 128.91, 128.04, 128.01, 127.93, 127.83, 127.62,
127.35, 127.11, 127.06, 126.88, 126.56, 126.49, 123.07, 122.68,
54.70, 43.30, 20.51 ppm. HRMS (ESI): calcd. for C28H23NO3SNa
[M + Na]+ 476.1296; found 476.1306.
Methyl 2-(2-Fluoro-5,6-dihydrophenanthridin-6-yl)acetate (3e):
Yield 67%. White solid, m.p. 101–103 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.64 (d, J = 7.9 Hz, 1 H), 7.38 (dd, J = 9.9, 2.7 Hz, 1
H), 7.33 (dd, J = 7.7, 1.4 Hz, 1 H), 7.26 (td, J = 7.4, 1.3 Hz, 1 H),
7.13 (d, J = 7.4 Hz, 1 H), 6.84 (td, J = 8.5, 2.8 Hz, 1 H), 6.62 (dd,
J = 8.7, 4.8 Hz, 1 H), 4.80 (dd, J = 10.4, 3.1 Hz, 1 H), 3.70 (s, 3
H), 2.84 (dd, J = 16.6, 10.4 Hz, 1 H), 2.42 (dd, J = 16.6, 3.1 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.92, 158.06, 138.21,
127.61, 127.49, 125.51, 122.37, 116.21, 116.16, 115.39, 115.09,
109.36, 109.05, 51.75, 51.19, 38.97 ppm.
2-(5,6-Dihydro-2-methyl-5-tosylphenanthridin-6-yl)-1-phenylethan-
one (6e): Yield 88 %. Yellow solid, m.p. 131–135 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.81 (d, J = 7.7 Hz, 1 H), 7.75 (d, J =
7.8 Hz, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.53–7.46 (m, 2 H), 7.42–
7.35 (m, 3 H), 7.24–7.19 (m, 2 H), 7.07 (m, 2 H), 6.95 (d, J =
8.0 Hz, 2 H), 6.69 (d, J = 7.9 Hz, 2 H), 6.04 (t, J = 6.9 Hz, 1 H),
3.34 (dd, J = 16.4, 5.7 Hz, 1 H), 3.00 (dd, J = 16.3, 7.8 Hz, 1 H),
2.41 (s, 3 H), 2.14 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
195.75, 142.23, 138.23, 136.81, 134.10, 133.77, 132.65, 130.38,
2-(5,6-Dihydrophenanthridin-6-yl)acetonitrile (3f): Yield 70%. Yel-
low solid, m.p. 131–133 °C. 1H NMR (300 MHz, CDCl3): δ = 7.77
(d, J = 7.74 Hz, 1 H), 7.73 (dd, J = 7.83, 1.26 Hz, 1 H), 7.40 (td,
J = 7.65, 1.29 Hz, 1 H), 7.32–7.26 (m, 1 H), 7.22–7.15 (m, 2 H), 129.21, 129.05, 128.91, 128.72, 128.61, 128.00, 127.93, 127.81,
6.91 (m, 1 H), 6.78 (m, 1 H), 4.76 (dd, J = 9.09, 4.59 Hz, 1 H), 127.65, 127.18, 127.02, 126.97, 126.85, 126.60, 126.50, 123.54,
2.68 (dd, J = 16.59, 9.09 Hz, 1 H), 2.48 (dd, J = 16.59, 4.56 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.39, 131.82, 130.06,
129.08, 128.29, 127.09, 125.81, 123.00, 122.48, 119.91, 119.45,
117.19, 115.69, 52.10, 24.81 ppm. HRMS (ESI): calcd. for
C15H12N2Na [M + Na]+ 243.0898; found 243.0902.
122.60, 54.63, 43.60, 20.91, 20.71 ppm. HRMS (ESI): calcd. for
C29H25NO3SNa [M + Na]+ 490.1453; found 490.1459.
2-(2-Fluoro-5,6-dihydro-5-tosylphenanthridin-6-yl)-1-phenylethanone
(6f): Yield 80 %. White solid, m.p. 104–107 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.81 (d, J = 7.3 Hz, 1 H), 7.75 (d, J =
1-(5,6-Dihydro-5-tosylphenanthridin-6-yl)propan-2-one
(6a/9a): 7.5 Hz, 1 H), 7.72–7.66 (m, 1 H), 7.55–7.45 (m, 2 H), 7.40–7.35 (m,
Yield by method a: 85%; yield by method b: 92%. Pale yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.74 (dd, J = 7.6, 1.4 Hz, 1 H),
7.57 (dd, J = 7.4, 1.7 Hz, 1 H), 7.43–7.29 (m, 2 H), 7.23–7.13 (m,
2 H), 7.32–7.26 (m, 2 H), 7.14–7.08 (m, 2 H), 6.94 (d, J = 8.1 Hz,
2 H), 6.70 (d, J = 8.0 Hz, 2 H), 6.08 (t, J = 6.9 Hz, 1 H), 3.33 (dd,
J = 16.4, 5.9 Hz, 1 H), 3.00 (dd, J = 16.5, 7.9 Hz, 1 H), 2.15 (s, 3
2 H), 7.13–7.02 (m, 2 H), 6.88 (d, J = 8.2 Hz, 2 H), 6.65 (d, J = H) ppm. 13C NMR (75 MHz, CDCl3): δ = 195.49, 142.58, 140.75,
8.1 Hz, 2 H), 5.82 (t, J = 7.2 Hz, 1 H), 2.67 (dd, J = 16.1, 7.4 Hz, 134.15, 132.90, 132.16, 130.91, 130.79, 129.53, 129.20, 128.08,
1 H), 2.47 (dd, J = 16.1, 7.1 Hz, 1 H), 2.10 (s, 3 H), 2.09 (s, 3 H)
127.94, 127.60, 127.25, 126.97, 126.85, 126.58, 126.50, 123.33,
ppm. 13C NMR (75 MHz, CDCl3): δ = 204.61, 142.61, 133.82, 122.90, 115.19, 114.88, 109.88, 109.51, 54.95, 43.91, 20.77 ppm.
133.34, 132.50, 129.51, 129.07, 128.88, 128.82, 128.73, 128.16,
127.88, 127.49, 127.26, 127.21, 126.51, 126.37, 123.13, 122.93,
54.19, 48.37, 29.88, 20.77 ppm.
HRMS (ESI): calcd. for C28H22NFO3SNa [M + Na]+ 494.1202;
found 494.1208.
Ethyl-2-(5,6-dihydro-5-tosylphenanthridin-6-yl)acetate (6g): Yield
90%. Yellow solid, m.p. 103–104 °C. 1H NMR (300 MHz, CDCl3):
δ = 7.77 (dd, J = 7.8, 1.2 Hz, 1 H), 7.57 (dd, J = 7.5, 1.5 Hz, 1 H),
7.42–7.29 (m, 2 H), 7.25–7.20 (m, 1 H), 7.16–7.04 (m, 3 H), 6.90
(d, J = 8.2 Hz, 2 H), 6.66 (d, J = 8.1 Hz, 2 H), 5.79 (t, J = 7.6 Hz,
1 H), 4.16 (q, J = 7.0 Hz, 2 H), 2.54 (dd, J = 15.0, 8.3 Hz, 1 H),
2.40 (dd, J = 15.0, 7.1 Hz, 1 H), 2.12 (s, 3 H), 1.27 (t, J = 7.1 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.16, 142.43, 133.58,
1-(5,6-Dihydro-2-methyl-5-tosylphenanthridin-6-yl)propan-2-one
(6b): Yield 92%. Yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.66
(d, J = 8.2 Hz, 1 H), 7.40 (s, 1 H), 7.26–7.17 (m, 3 H), 7.16–7.20
(m, 2 H), 6.94 (d, J = 8.3 Hz, 2 H), 6.70 (d, J = 8.0 Hz, 2 H), 5.81
(t, J = 7.2 Hz, 1 H), 2.71 (dd, J = 16.2, 7.4 Hz, 1 H), 2.50 (dd, J
= 16.1, 7.2 Hz, 1 H), 2.44 (s, 3 H), 2.16 (s, 3 H), 2.14 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 204.61, 142.32, 137.00, 133.89,
133.52, 130.03, 129.37, 129.16, 129.02, 128.75, 127.81, 127.26, 133.53, 133.23, 132.46, 129.26, 129.02, 129.00, 128.13, 127.82,
127.04, 126.78, 126.60, 126.45, 123.61, 122.62, 122.02, 54.95, 48.37, 127.39, 127.30, 127.10, 126.53, 126.18, 126.16, 123.02, 122.77,
29.88, 20.91, 20.72 ppm. HRMS (ESI): calcd. for C24H23NO3SNa 60.27, 55.39, 39.94, 20.90, 13.76 ppm.
[M + Na]+ 428.1296; found 428.1301.
Ethyl 2-(5,6-Dihydro-2-methyl-5-tosylphenanthridin-6-yl)acetate
1-(2-Fluoro-5,6-dihydro-5-tosylphenanthridin-6-yl)propan-2-one (6c): (6h): Yield 82%. Yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.64
Yield 83%. Yellow solid, m.p. 123–125 °C. 1H NMR (300 MHz,
(d, J = 8.2 Hz, 1 H), 7.37 (s, 1 H), 7.25–7.15 (m, 2 H), 7.16–7.09
CDCl3): δ = 7.75 (dd, J = 8.9, 5.3 Hz, 1 H), 7.26 (dd, J = 9.33, (m, 3 H), 6.92 (d, J = 8.0 Hz, 2 H), 6.67 (d, J = 8.0 Hz, 2 H), 5.76
3.0 Hz, 1 H), 7.21 (s, 1 H), 7.19–7.06 (m, 4 H), 6.91 (d, J = 8.3 Hz,
2 H), 6.69 (d, J = 8.0 Hz, 2 H), 5.84 (t, J = 7.2 Hz, 1 H), 2.68 (dd,
(t, J = 7.6 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 2.53 (dd, J = 14.9,
8.3 Hz, 1 H), 2.46–2.33 (m, 4 H), 2.13 (s, 3 H), 1.27 (t, J = 7.0 Hz,
J = 16.2, 7.3 Hz, 1 H), 2.50 (dd, J = 16.2, 7.3 Hz, 1 H), 2.14 (s, 3 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.34, 142.33, 136.88,
H), 2.12 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 204.10, 133.65, 133.35, 132.32, 129.87, 129.19, 129.09, 129.05, 128.93,
163.02, 159.84, 142.70, 133.94, 133.12, 131.42, 131.31, 130.90, 128.78, 127.81, 127.20, 126.85, 126.54, 126.18, 123.55, 122.67,
130.77, 128.15, 127.95, 127.28, 126.59, 122.88, 115.28, 115.01, 60.36, 55.33, 39.81, 20.88, 20.73, 13.80 ppm.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42913
/KAP1
Date: 07-10-14 16:41:29
Pages: 9
X. Bao, W. Yao, Q. Zhu, Y. Xu
FULL PAPER
Ethyl 2-(5-Tosyl-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinolin-4-
yl)acetate (9b): Yield 81%. White solid, m.p. 100–101 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.70 (dd, J = 1.3, 7.8 Hz, 1 H), 7.20–7.32
2 H), 5.82 (t, J = 7.14 Hz, 1 H), 2.7 (dd, J = 6.54, 16.5 Hz, 1 H),
2.48 (dd, J = 7.77, 16.47 Hz, 1 H), 2.18 (s, 3 H), 2.08 (s, 3 H) ppm.
13C NMR (75 MHz,CDCl3): δ = 204.47, 163.59, 160.33, 142.87,
(m, 2 H), 7.15 (d, J = 8.28 Hz, 2 H), 7.04 (d, J = 8.16 Hz, 2 H), 133.29, 132.78, 129.69, 128.98, 128.86, 128.41, 128.30, 127.94,
6.9 (dd, J = 1.53, 7.23 Hz, 1 H), 5.25 (t, J = 7.62 Hz, 1 H), 4.12–
4.23 (m, 2 H), 2.46 (dd, J = 6.6, 2.4 Hz, 1 H), 2.42 (m, 1 H), 2.26
(m, 2 H), 2.33 (s, 3 H), 2.11 (m, 1 H), 1.81 (m, 2 H), 1.45 (m, 1
H), 1.30 (t, J = 7.17 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 169.44, 142.66, 137.16, 134.90, 132.66, 128.82, 128.55, 128.31,
128.14, 126.76, 126.58, 126.36, 122.37, 60.36, 53.08, 37.54, 34.06,
29.44, 21.88, 20.89, 13.73 ppm. HRMS (ESI): calcd. for
C23H25NO4SNa [M + Na]+ 434.1397; found 411.1508.
127.35, 126.57, 123.23, 114.23, 113.93, 109.63, 109.32, 53.73, 48.36,
29.84, 20.71 ppm. HRMS (ESI): calcd. for C23H20FNO3SNa [M +
Na]+ 432.1043; found 409.1151.
1-(5-Tosyl-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinolin-4-yl)propan-
2-one (9h): Yield 96 %. White solid, m.p. 86–87 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.69 (d, J = 7.35 Hz, 1 H), 7.22–7.33 (m,
2 H), 7.15 (d, J = 8.28 Hz, 2 H), 7.05 (d, J = 8.04 Hz, 2 H), 5.25
(t, J = 6.54 Hz, 1 H), 2.7 (dd, J = 8.19, 15.6 Hz, 1 H), 2.38 (dd, J
= 6.06, 15.3 Hz, 1 H), 2.36–2.45 (m, 2 H), 2.33 (s, 3 H), 2.20 (s, 3
H), 2.02–2.15 (m, 1 H), 1.71–1.87 (m, 2 H), 1.35–1.48 (m, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 205.07, 142.79, 137.85,
134.71, 132.32, 130.98, 128.78, 128.25, 128.19, 126.74, 26.37,
122.45, 52.60, 46.02, 34.13, 29.99, 29.41, 21.82, 20.90 ppm. HRMS
(ESI): calcd. for C22H23NO3SNa [M + Na]+ 404.1291; found
381.1398.
Ethyl 2-(5-Tosyl-5,6,7,8,9,10-hexahydrophenanthridin-6-yl)acetate
(9c): Yield 83%. Yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.66
(dd, J = 1.59, 7.71 Hz, 1 H), 7.22–7.32 (m, 2 H), 7.16 (d, J =
8.19 Hz, 2 H), 7.05 (d, J = 8.13 Hz, 3 H), 4.83 (dd, J = 9.54,
4.74 Hz, 1 H), 4.20 (q, J = 7.17 Hz, 2 H), 2.33 (s, 3 H), 2.22–2.29
(m, 2 H), 2.17–2.21 (m, 1 H), 2.02–2.08 (m, 1 H), 1.69–1.78 (m, 1
H), 1.41–1.61 (m, 3 H), 1.32 (t, J = 7.44 Hz, 3 H), 0.85–0.99 (m, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.61, 142.72, 135.18,
131.50, 131.05, 130.84, 128.26, 126.71, 126.53, 126.29, 125.57,
121.46, 60.37, 55.31, 36.56, 27.77, 23.42, 21.32, 20.87, 13.78 ppm.
HRMS (ESI): calcd. for C24H27NO4SNa [M + Na]+ 448.1553;
found 425.1661.
1-(5-Tosyl-5,6,7,8,9,10-hexahydrophenanthridin-6-yl)propan-2-one
(9i): Yield 97 %. White solid, m.p. 123–124 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.65 (dd, J = 1.92, 7.11 Hz, 1 H), 7.23–
7.34 (m, 2 H), 7.16 (d, J = 8.25 Hz, 2 H), 7.06 (d, J = 7.90 Hz, 3
H), 4.82 (dd, J = 4.08, 9.81 Hz, 1 H), 2.42 (dd, J = 9.93, 14.82 Hz,
1 H), 2.33 (s, 3 H), 2.29 (m, 1 H), 2.24 (s, 3 H), 2.12–2.20 (m, 1
H), 1.97–2.10 (m, 1 H), 1.66–1.80 (m, 1 H), 1.53–1.63 (m, 2 H),
1.25–1.5 (m, 3 H), 0.8–1.0 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 205.43, 142.86, 134.99, 132.02, 131.05, 130.97, 128.31,
128.22, 126.77, 126.70, 126.33, 125.36, 121.57, 54.96, 44.73, 29.98,
27.74, 23.42, 21.32, 20.89 ppm. HRMS (ESI): calcd. for
C23H25NO3SNa [M + Na]+ 418.1447; found 395.1557.
Ethyl 2-(5-Tosyl-4,5-dihydrothieno[2,3-c]quinolin-4-yl)acetate (9d):
Yield 80%. Yellow oil. 1H NMR (300 MHz, CDCl3): δ = 7.78–7.81
(m, 1 H), 7.31–7.36 (m, 3 H), 7.01 (d, J = 5.16 Hz, 2 H), 6.97 (s, 1
H), 6.80 (d, J = 5.34 Hz, 1 H), 6.78 (s, 1 H), 6.02 (t, J = 7.62 Hz,
1 H), 4.18 (q, J = 7.14 Hz, 2 H), 2.65 (dd, J = 7.11, 15.39 Hz, 1
H), 2.48 (dd, J = 8.1, 15.42 Hz, 1 H), 2.19 (s, 3 H), 1.29 (t, J =
7.14 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.97,
142.60, 133.43, 133.09, 132.04, 130.46, 128.95, 127.90, 127.32,
127.20, 127.05, 126.30, 124.10, 122.64, 121.46, 60.52, 51.69, 40.24,
20.81, 13.70 ppm. HRMS (ESI): calcd. for C22H21NO4S2Na [M +
Na]+ 450.0804; found 427.0913.
Ethyl 2-(8,9-Dimethoxy-5-tosyl-5,6-dihydrophenanthridin-6-yl)acet-
ate (9j): Yield 84 %. Yellow solid, m.p. 140–141 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.74–7.77 (m, 1 H), 7.45–7.50 (m, 1 H),
7.32–7.36 (m, 2 H), 6.93 (d, J = 8.25 Hz, 2 H), 6.73 (d, J = 8.07 Hz,
2 H), 6.69 (d, J = 6.99 Hz, 2 H), 5.72 (t, J = 7.8 Hz, 1 H), 4.17 (q,
J = 7.14 Hz, 2 H), 3.9 (s, 3 H), 3.81 (s, 3 H), 2.55 (dd, J = 7.98,
15.06 Hz, 1 H), 2.41 (dd, J = 7.23, 15.18 Hz, 1 H), 2.17 (s, 3 H),
1.28 (t, J = 7.11 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
169.87, 148.77, 148.44, 142.29, 134.20, 133.70, 131.81, 129.46,
129.35, 129.01, 127.72, 127.34, 126.61, 126.45, 122.35, 122.04,
109.23, 105.94, 60.35, 55.66, 55.56, 54.93, 9.87, 20.70, 13.74 ppm.
HRMS (ESI): calcd. for C26H27NO6SNa [M + Na]+ 504.1451;
found 481.1581.
1-(6-Tosyl-5,6-dihydrobenzo[h][1,6]naphthyridin-5-yl)propan-2-one
(9e): Yield 85 %. Yellow solid, m.p. 169–170 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.30 (d, J = 3.96 Hz, 1 H), 8.13 (d, J =
7.41 Hz, 1 H), 7.77 (d, J = 7.86 Hz, 1 H), 7.48–7.54 (m, 2 H), 7.42
(t, J = 7.77 Hz, 1 H), 6.95–7.02 (m, 3 H), 5.84 (dd, J = 5.76,
8.37 Hz, 2 H), 2.85 (dd, J = 5.64, 17.04 Hz, 1 H), 2.58 (dd, J =
8.49, 16.98 Hz, 1 H), 2.13 (s, 3 H), 2.05 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 203.04, 148.06, 147.01, 143.07, 134.47,
134.23, 133.58, 129.91, 129.03, 128.95, 128.22, 128.14, 127.29,
126.56, 124.51, 121.86, 53.56, 48.31, 29.85, 20.75 ppm. HRMS
(ESI): calcd. for C22H21N2O3S [M + H]+ 393.1267; found 392.1197.
1-(8,9-Dimethoxy-5-tosyl-5,6-dihydrophenanthridin-6-yl)propan-2-
one (9k): Yield 87 %. Yellow solid, m.p. 166–167 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.74–7.78 (m, 1 H), 7.45–7.51 (m, 1 H),
7.32–7.37 (m, 2 H), 6.93 (d, J = 8.25 Hz, 2 H), 6.76 (s, 1 H), 6.73
(d, J = 8.07 Hz, 2 H), 6.66 (s, 1 H), 5.75 (t, J = 7.05 Hz, 1 H), 3.91
(s, 3 H), 3.80 (s, 3 H), 2.73 (dd, J = 6.6, 16.44 Hz, 1 H), 2.52 (dd,
J = 7.68, 16.47 Hz, 1 H), 2.17 (s, 3 H), 2.10 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 204.59, 148.74, 148.30, 142.36,
133.52, 131.95, 129.60, 128.86, 127.73, 127.28, 127.18, 126.96,
126.60, 122.44, 121.75, 109.55, 105.88, 55.66, 55.56, 54.05, 48.40,
29.94, 20.68 ppm. HRMS (ESI): calcd. for C25H25NO5SNa [M +
Na]+ 474.1346; found 451.1455.
Ethyl 2-(9-Fluoro-5-tosyl-5,6-dihydrophenanthridin-6-yl)acetate (9f):
Yield 85%. White solid, m.p. 128–129 °C. H NMR (300 MHz,
1
CDCl3): δ = 7.79 (dd, J = 1.4, 8.01 Hz, 1 H), 7.48–7.52 (m, 1 H),
7.41–7.46 (m, 1 H), 7.33–7.39 (m, 1 H), 6.89–6.94 (m, 3 H), 6.80–
6.87 (m, 1 H), 6.73 (d, J = 8.13 Hz, 2 H), 5.78 (t, J = 7.62 Hz, 1
H), 4.15 (q, J = 13.2 Hz, 2 H), 2.54 (dd, J = 7.8, 15.15 Hz, 1 H),
2.37 (dd, J = 7.5, 15.12 Hz, 1 H), 2.18 (s, 3 H), 1.26 (t, J = 7.14 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.02, 163.69, 160.44,
142.81, 133.40, 132.57, 131.22, 131.11, 129.09, 128.87, 128.45,
128.05, 127.91, 127.30, 126.55, 123.18, 114.21, 113.92, 109.70,
109.40, 60.39, 54.61, 39.82, 20.70, 13.70 ppm. HRMS (ESI): calcd.
for C24H22FNO4SNa [M + Na]+ 462.1146; found 439.12.
1-(9-Fluoro-5-tosyl-5,6-dihydrophenanthridin-6-yl)propan-2-one Ethyl 2-(6-Tosyl-5,6-dihydrobenzo[h][1,6]naphthyridin-5-yl)acetate
1
(9g): Yield 96 %. White solid, m.p. 150–151 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.78 (d, J = 8.04 Hz, 1 H), 7.35–7.53 (m,
(9l): Yield 86%. Yellow solid, m.p. 92–93 °C. H NMR (300 MHz,
CDCl3): δ = 8.32–8.36 (m, 1 H), 8.11–8.14 (m, 1 H), 7.77–7.81 (m,
3 H), 7.17–7.22 (m, 1 H), 6.79–6.92 (m, 4 H), 6.72 (d, J = 8.04 Hz, 1 H), 7.39–7.54 (m, 3 H), 7.02–7.05 (m, 1 H), 6.98 (d, J = 8.13 Hz,
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42913
/KAP1
Date: 07-10-14 16:41:29
Pages: 9
Synthesis of 6-Substituted Phenanthridine Derivatives
2 H), 6.76 (d, J = 7.92 Hz, 2 H), 5.82 (t, J = 7.53 Hz, 1 H), 4.14
(m, 2 H), 2.69 (dd, J = 7.32, 15.51 Hz, 1 H), 2.47 (dd, J = 7.95,
15.36 Hz, 1 H), 2.15 (s, 3 H), 1.25 (t, J = 6.66 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.94, 148.38, 147.30, 143.01,
133.95, 133.84, 133.63, 129.88, 128.99, 128.26, 128.18, 127.25,
126.94, 126.54, 124.42, 121.82, 60.48, 54.60, 39.68, 20.74,
13.66 ppm. HRMS (ESI): calcd. for C23H22N2O4SNa [M + Na]+
445.1192; found 422.1307.
Acknowledgments
The authors appreciate the support by Lidan Sun for her work on
the LC-MS analysis, and from Tingting Liang and Jingshang Ruan
for their work on the experimental part.
[1] For reviews, see: a) R. S. Theobald, K. Schofield, Chem. Rev.
1950, 46, 170–189; b) S. D. Phillips, R. N. Castle, J. Heterocycl.
Chem. 1981, 18, 223–232; c) T. Ishikawa, Med. Res. Rev. 2001,
21, 61–72.
Ethyl 2-(9-Methyl-6-tosyl-5,6-dihydrobenzo[h][1,6]naphthyridin-5-
1
yl)acetate (9m): Yield 75%. Yellow solid, m.p. 94–95 °C. H NMR
(300 MHz, CDCl3): δ = 8.31–8.34 (m, 1 H), 7.93 (s, 1 H), 7.67 (d,
J = 8.16 Hz, 1 H), 7.43–7.46 (m, 1 H), 7.29–7.33 (m, 1 H), 6.97–
7.04 (m, 3 H), 6.77 (d, J = 8.22 Hz, 2 H), 5.79 (t, J = 7.53 Hz, 1
H), 4.14 (m, 2 H), 2.67 (dd, J = 7.32, 15.36 Hz, 1 H), 2.45 (dd, J
= 7.92, 15.27 Hz, 1 H), 2.44 (s, 3 H), 2.14 (s, 3 H), 1.24 (t, J =
7.08 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.99,
148.28, 147.50, 142.90, 137.34, 133.88, 133.63, 131.41, 130.78,
128.61, 128.35, 128.16, 128.13, 126.59, 124.65, 121.68, 60.45, 54.62,
39.62, 20.75, 20.70, 13.67 ppm. HRMS (ESI): calcd. for
C24H24N2O4SNa [M + Na]+ 459.1349; found 436.1463.
[2] For examples, see: a) O. B. Abdel-Halim, T. Morikawa, S.
Ando, H. Matsuda, M. Yoshikawa, J. Nat. Prod. 2004, 67,
1119–1124; b) P. J. Houghton, Y. Ren, M.-J. Howes, Nat. Prod.
Rep. 2006, 23, 181–199; c) A. D. C. Parenty, L. V. Smith, K. M.
Guthrie, D.-L. Long, J. Plumb, R. Brown, L. Cronin, J. Med.
Chem. 2005, 48, 4504–4506; d) D. Lamoral-Theys, A. Andolfi,
G. Van Goietsenoven, A. Cimmino, B. Le Calvé, N. Wauthoz,
V. r. Mégalizzi, T. Gras, C. l. Bruyère, J. Dubois, V. R. Mathieu,
A. Kornienko, R. Kiss, A. Evidente, J. Med. Chem. 2009, 52,
6244–6256.
[3] S. S. Lee, U. Venkatesham, C. P. Rao, S. H. Lam, J. H. Lin,
Bioorg. Med. Chem. 2007, 15, 1034–1043.
[4] J. Eles, G. Beke, I. Vago, E. Bozo, J. Huszar, A. Tarcsay, S.
Kolok, E. Schmidt, M. Vastag, K. Hornok, S. Farkas, G. Dom-
any, G. M. Keseru, Bioorg. Med. Chem. Lett. 2012, 22, 3095–
3099.
[5] For phenanthridine synthesis through iron-catalyzed intramo-
lecular N-arylation of O-acetyl oxime, see: I. Deb, N. Yoshikai,
Org. Lett. 2013, 15, 4254–4257.
[6] For phenanthridine synthesis via [2+2+2] cyclotrimerization
reactions, see: L. Sripada, J. A. Teske, A. Deiters, Org. Biomol.
Chem. 2008, 6, 263–265.
[7] For the synthesis of phenanthridines and analogues via Suzuki
coupling and condensation, see: S. Dhara, M. Ghosh, J. K.
Ray, Synlett 2013, 24, 2263–2265.
Ethyl 2-(8-Methyl-5-tosyl-2,3,4,5-tetrahydro-1H-cyclopenta[c]quin-
1
olin-4-yl)acetate (9n): Yield 77%. Yellow solid, m.p. 97–98 °C. H
NMR (300 MHz, CDCl3): δ = 7.57 (d, J = 8.04 Hz, 1 H), 7.16 (d,
J = 7.92 Hz, 1 H), 7.03–7.11 (m, 3 H), 6.71 (s, 1 H), 5.2 (t, J =
6.84 Hz, 1 H), 6.15–6.19 (m, 2 H), 5.79 (t, J = 7.53 Hz, 1 H), 4.14
(m, 2 H), 2.32–2.48 (m, 4 H), 2.34 (s, 3 H), 2.33 (s, 3 H), 2.02–2.10
(m, 1 H), 1.68–1.87 (m, 2 H), 1.36–1.48 (m, 1 H), 1.30 (t, J =
7.05 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.51,
142.56, 136.98, 136.37, 134.91, 132.74, 128.41, 128.30, 128.13,
128.09, 127.45, 126.37, 122.96, 60.33, 53.05, 37.42, 34.04, 29.42,
21.88, 20.89, 20.70, 13.74 ppm. HRMS (ESI): calcd. for
C24H27NO4SNa [M + Na]+ 448.1559; found 425.1667.
[8] For the synthesis of 5,6-dihydrophenanthridines via N,O-acetal
TMS ethers, see: W.-I. Lee, J.-W. Jung, J. Jang, H. Yun, Y.-G.
Suh, Tetrahedron Letters 2013, 54, 5167–5171.
Ethyl 2-(9-Fluoro-6-tosyl-5,6-dihydrobenzo[h][1,6]naphthyridin-5-
yl)acetate (9o): Yield 73%. White solid, m.p. 92–93 °C. H NMR
1
(300 MHz, CDCl3): δ = 8.31–8.34 (m, 1 H), 7.74–7.85 (m, 2 H),
7.46–7.50 (m, 1 H), 7.16–7.23 (m, 1 H), 7.04–7.09 (m, 1 H), 6.98
(d, J = 8.16 Hz, 2 H), 6.78 (d, J = 8.04 Hz, 2 H), 5.82 (t, J =
7.56 Hz, 1 H), 4.09–4.19 (m, 2 H), 2.67 (dd, J = 7.38, 15.36 Hz, 1
H), 2.46 (dd, J = 7.83, 15.36 Hz, 1 H), 2.16 (s, 3 H), 1.25 (t, J =
7.14 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.80,
163.12, 159.89, 148.47, 146.41, 143.20, 133.90, 133.28, 130.30,
130.19, 129.79, 129.76, 128.37, 128.25, 126.57, 122.42, 117.03,
116.72, 111.09, 110.76, 60.55, 54.58, 39.70, 20.76, 13.66 ppm.
HRMS (ESI): calcd. for C23H22FN2O4S [M + H]+ 441.1283; found
440.121.
[9] For a Suzuki cross-coupling and intramolecular aza-Michael
addition reaction sequence towards the synthesis of 1,10b-epi-
7-deoxypancratistatins and their cytotoxicity studies, see: G.
Pandey, M. Balakrishnan, P. S. Swaroop, Eur. J. Org. Chem.
2008, 5839–5847 .
[10] B. S. Kim, S. Y. Lee, S. W. Youn, Chem. Asian J. 2011, 6, 1952–
1957.
[11] N. Della Ca, E. Motti, M. Catellani, Adv. Synth. Catal. 2008,
350, 2513–2516.
[12] M. Miura, T. Tsuda, T. Satoh, S. Pivsa-Art, M. Nomura, J.
Org. Chem. 1998, 63, 5211–5215.
[13] J. K. Augustine, A. Bombrun, P. Alagarsamy, A. Jothi, Tetrahe-
dron Lett. 2012, 53, 6280–6287.
Ethyl 2-(2-Fluoro-8,9-dimethoxy-5-tosyl-5,6-dihydrophenanthridin-
6-yl)acetate (9p): Yield 72%. White solid, m.p. 149–151 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.70–7.75 (m, 1 H), 7.13–7.17 (m, 1
H), 7.02–7.08 (m, 1 H), 6.92 (d, J = 7.89 Hz, 2 H), 6.75 (d, J =
8.07 Hz, 2 H), 6.72 (s, 1 H), 6.58 (s, 1 H), 5.72 (t, J = 7.53 Hz, 1
H), 4.13–4.21 (m, 2 H), 3.91 (s, 3 H), 3.81 (s, 3 H), 2.52 (dd, J =
8.13, 14.94 Hz, 1 H), 2.41 (dd, J = 7.08, 15.06 Hz, 1 H), 2.17 (s, 3
H), 1.28 (t, J = 7.02 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 169.19, 163.03, 159.01, 149.30, 148.50, 142.49, 134.19, 133.34,
130.93, 130.82, 127.80, 127.32, 126.62, 126.56, 121.16, 114.32,
114.02, 109.16, 108.81, 105.86, 60.42, 55.69, 55.59, 54.94, 39.83,
20.71, 13.74 ppm. HRMS (ESI): calcd. for C26H26FNO6SNa [M +
Na]+ 522.1358; found 499.1466.
[14] For examples, see: a) S. Belot, K. A. Vogt, C. Besnard, N.
Krause, A. Alexakis, Angew. Chem. Int. Ed. 2009, 48, 8923–
8926; Angew. Chem. 2009, 121, 9085–9088; b) G. E. Ferris, K.
Hong, I. A. Roundtree, J. P. Morken, J. Am. Chem. Soc. 2013,
135, 2501–2504; c) F. Zhou, M. Yang, X. Lu, Org. Lett. 2009,
11, 1405–1408; d) N.-W. Tseng, J. Mancuso, M. Lautens, J. Am.
Chem. Soc. 2006, 128, 5338–5339; e) S. Ma, N. Jiao, Angew.
Chem. Int. Ed. 2002, 41, 4737–4740; Angew. Chem. 2002, 114,
4931–4934; f) M. C. Willis, G. N. Brace, I. P. Holmes, Angew.
Chem. Int. Ed. 2005, 44, 403–406; Angew. Chem. 2005, 117,
407–410.
[15] For a review about tandem reactions, see: J.-C. Wasilke, S. J.
Obrey, R. T. Baker, G. C. Bazan, Chem. Rev. 2005, 105, 1001–
1020.
[16] Q. Zhu, X. Wang, Y. Xu, Eur. J. Org. Chem. 2012, 1112–1114.
[17] Y.-Y. Liu, R.-J. Song, C.-Y. Wu, L.-B. Gong, M. Hu, Z.-Q.
Wang, Y.-X. Xie, J.-H. Li, Adv. Synth. Catal. 2012, 354, 347–
353.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all new com-
pounds.
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O42913
/KAP1
Date: 07-10-14 16:41:29
Pages: 9
X. Bao, W. Yao, Q. Zhu, Y. Xu
FULL PAPER
[18] N. Della Ca, E. Motti, A. Mega, M. Catellani, Adv. Synth. Ca-
tal. 2010, 352, 1451–1454.
[19] C. Amatore, G. Le Duc, A. Jutand, Chem. Eur. J. 2013, 19,
10082–10093.
[20] A. J. J. Lennox, G. C. Lloyd-Jones, Angew. Chem. Int. Ed. 2013,
52, 7362–7370; Angew. Chem. 2013, 125, 7506–7515.
Received: July 12, 2014
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42913
/KAP1
Date: 07-10-14 16:41:29
Pages: 9
Synthesis of 6-Substituted Phenanthridine Derivatives
Heterocycle Synthesis
X. Bao, W. Yao, Q. Zhu,* Y. Xu* .... 1–9
Synthesis of 6-Substituted Phenanthridine
Derivatives by Palladium-Catalysed Dom-
ino Suzuki–Miyaura/Aza-Michael Reac-
tions
A domino reaction involving a palladium-
catalysed Suzuki–Miyaura reaction fol-
lowed by an intramolecular aza-Michael
addition is presented. This allows the for-
mation of a C–C bond and a C–N bond
under mild conditions in one pot.
Keywords: Homogeneous catalysis / Pal-
ladium / Domino reactions / Cyclization /
Nitrogen heterocycles
Eur. J. Org. Chem. 0000, 0–0
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