Synthesis of N-substituted benzo[c][1,7]- and benzo[c][1,8] phenanthrolin-(5H)-6-ones through a Pd-mediated Suzuki-Miyaura heteroaryl-aryl coupling reaction

Article abstract of DOI:10.1016/j.tet.2009.09.110

In the course of the search for non-camptothecin topoisomerase I inhibitors we have undertaken the synthesis of N-substituted benzo[c][1,7]- and benzo[c][1,8]phenanthrolinone derivatives. An intermolecular Suzuki-Miyaura heteroaryl-aryl coupling reaction was planned as the key step. Then a nitro reduction followed by a concomitant lactamization achieved the construction of the tetracycle structures. This methodology permitted a rapid and efficient elaboration of biologically potent compounds.

Full text of DOI:10.1016/j.tet.2009.09.110

Tetrahedron 65 (2009) 10009–10015
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of N-substituted benzo[c][1,7]- and benzo[c][1,8] phenanthrolin-
(5H)-6-ones through a Pd-mediated Suzuki–Miyaura
heteroaryl-aryl coupling reaction
*
`
´
Constance Genes, Sylvie Michel, François Tillequin, François-Hugues Poree
Universite´ Paris Descartes, Laboratoire de Pharmacognosie UMR CNRS 8638, 4 Avenue de l’Observatoire, F-75006 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
In the course of the search for non-camptothecin topoisomerase I inhibitors we have undertaken the
synthesis of N-substituted benzo[c][1,7]- and benzo[c][1,8]phenanthrolinone derivatives. An in-
termolecular Suzuki–Miyaura heteroaryl-aryl coupling reaction was planned as the key step. Then a nitro
reduction followed by a concomitant lactamization achieved the construction of the tetracycle structures.
This methodology permitted a rapid and efficient elaboration of biologically potent compounds.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 18 August 2009
Received in revised form
24 September 2009
Accepted 28 September 2009
Available online 1 October 2009
Y
Y
1. Introduction
Z
Z
O
O
O
O
Benzo[c]phenanthridine alkaloids have a long history in me-
dicinal use dating back to 1896 when extracts of Chelidonium majus
were reported to treat cancer.1 Among the different compounds
isolated, sanguinarine 1 is currently used for its antibacterial
properties, and nitidine 2 and fagaronine 3 are regarded as model
compounds for the conception of DNA topoisomerase I inhibitors
presenting a non-camptothecin skeleton (Fig. 1).2 Herein, we wish
to report our efforts towards the preparation of N-substituted
benzo[c][1,7]- and benzo[c][1,8]phenanthrolinones (BZP) as func-
tionalized aza-analogues of 2 and 3 via a concise synthetic ap-
proach (Fig. 2).
N
N
R
R
O
O
Y = CH, Z = N,
Y = N, Z = CH,
Y = CH, Z = N,
Y = N, Z = CH,
R: H, (CH ) N(CH ) or (CH ) N(C H )
R: H, (CH ) N(CH ) or (CH ) N(C H )
2 n 3 2 2 n 2 5 2
2 n
3 2
2 n
2
5 2
n = 2, 3
n = 2, 3
Figure 2. 1,7- and 1,8-benzo[c]phenanthrolinones.
Thus, ring C closure could be envisaged by a nitro reduction
followed by an in situ lactamization from the corresponding het-
eroaryl-aryl compound (Scheme 1). An intermolecular Suzuki–
Miyaura cross-coupling reaction between an aryl boronate ester
corresponding to cycle D and a quinoline or an isoquinoline func-
tionalized in position 6 representing AB motif was chosen as a very
attractive methodology to construct the C10a–C10b bond.4,5
OH
O
O
O
O
MeO
MeO
MeO
MeO
OMe
N+
N+
N+
O
O
Sanguinarine 1
Nitidine 2
Fagaronine 3
Figure 1. Examples of benzo[c]phenanthridine alkaloids.
8: X = OTf, Y = N, Z = CH
9: X = Br, Y = CH, Z = N
In a preliminary work, the synthesis of benzo[c][1,8]phenan-
1
12
Y
A
Y
11
Y
throlinone backbone 4 was described in low yields through an
intramolecular cyclization of a 2-bromo N-(isoquinol-5-yl)benza-
mide.3 Further efforts in this way were unfruitful. We report in this
paper a new synthetic approach based on an intermolecular Pd-
mediated biaryl coupling reaction permitting the efficient elabora-
tion of functionalized BZP.
Z
Z
Z
10
B
R1
R2
3
R1
R2
X
4
+
D
C
NH
5
NO2
COOMe
NO2
R1
R2
B
7
[Pd°]
Reduction
O
lactamization
COOMe
4: R1 = R2 = OCH3, Y = N, Z = CH
5: R1 = R2 = OCH3, Y = CH, Z = N
6: R1, R2 = OCH2O, Y = N, Z = CH
7: R1, R2 = OCH2O, Y = CH, Z = N
10: R1 = R2 = OCH3
11: R1, R2 = OCH2O
* Corresponding author.
Scheme 1. Retrosynthesis.
´
E-mail address: francois-hugues.poree@parisdescartes.fr (F.-H. Poree).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.110

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C. Gene`s et al. / Tetrahedron 65 (2009) 10009–10015
Table 1
2. Results and discussion
Systematic study in methylenedioxy ‘series’
[Pd°]
CH3CN, 120 °C
18 h
Functionalized AB units correspond to quinoline 8 or to iso-
quinoline 9 substituted in position 5 by a nitro group and in posi-
tion 6, respectively, by a halogen atom or a triflate. These two
different compounds were easily prepared (Scheme 2). Concerning
the quinoline series, nitration with KNO3 in sulfuric acid of com-
mercially available 6-hydroxyquinoline 12 provided exclusively the
corresponding 5-nitro 6-hydroxyquinoline 13 in good yields. Then
the hydroxy function was converted into the corresponding triflate,
upon treatment with triflic anhydride in CH2Cl2 in the presence of
pyridine.6
N
N
O
B
O
O
O
O
+
O
TfO
NO2
COOMe
18
Base
NO2
COOMe
11
8
,b
Entry
Base
Yielda
PdCl2(dppf)
PdCl2(PPh3)2
Pd(PPh3)4
1
2
3
4
5
6
KOAc
Et3N
NaOH
Cs2CO3
K2CO3
NaHCO3
No reaction
No reaction
49%
Degradation
37%
Degradation
Degradation
21%
Degradation
No reaction
Degradation
12%
H2SO4cc
Tf2O, pyridine
N
N
N
14%
46%
38%
50%
KNO3
76%
CH2Cl2, r.t.
80 %
HO
TfO
HO
No reaction
60%
NO2
NO2
a
Isolated yields.
12
13
8
b
Reaction conditions: Pd complex (10 mol %), base (3 equiv), 8 (1 equiv) 11
(1.5 equiv), CH3CN, 120 ꢀC for 18 h.
O
H2SO4cc
H2N
CHO a )
b )
O
N
N
Br
P(OMe)3, TiCl4 Br
38%
KNO3
93%
Br
permitting a direct comparison of the Pd/base systems. Different
reactivities were observed: the reactionproceeded, did not take place
(PdCl2(dppf) and Pd(PPh3)4), or degradation was observed
(PdCl2(PPh3)2 and Pd(PPh3)4).12 With all Pd complexes, KOAc was not
appropriate, giving no reaction or degradation products (entry 1). In
contrast, K2CO3 gave more satisfying results, providing the cross-
coupled product 18 in all cases in moderate 46%, 21% and 38% yields,
respectively (entry 5). Besides other carbonate bases, such as Cs2CO3
and NaHCO3, are also tolerated since they provided the cross-coupled
product 18 with two of the three Pd complexes (entries 4 and 6). The
use of organic mild base Et3N seemed limited to one Pd complex
(entry 2). A stronger base, such as NaOH, gave an interesting good
result with PdCl2(dppf) (entry 3). Unfortunately whatever the con-
ditions employed, the yield of the reaction is limited to 60% (entry 6),
which is acceptable for this type of aryl-heterocycle cross-coupling
reaction.
We examined the possibility of combining the two steps, that is
introduction of the boron moiety and cross-coupling. The
PdCl2(dppf)/NaHCO3 system retained for the boronate preparation
proved to be unsuccessful for the biaryl connection (entry 6).
Moreover, the efficient PdCl2(PPh3)2/NaHCO3 system of the study
(entry 6) only furnished de-brominated benzoates when applied to
methyl esters 16 and 17.
NO2
14
15
9
Scheme 2. AB Units.
Preparation of 6-bromo 5-nitro isoquinoline 9 started from 4-
bromobenzaldehyde 14.7 Reaction with amino acetaldehyde diethyl-
acetal furnished the corresponding imine, which was cyclized
with trimethylphosphite and titanium chloride in 38% overall yields.
Selective nitration at position 5 was realized as previously described
(Scheme 2).
Finally quinoline 8 was prepared in two steps with 61% yield and
isoquinoline 9 in 35% yield over three steps.
Pinacol boronates 10 and 11 were envisioned as partners for the
biaryl coupling with unit AB (Scheme 1). Preparation of these
compounds was envisaged via a Pd catalyzed coupling reaction
(Scheme 3).8 Several experimental conditions were screened and
the PdCl2(dppf)/NaHCO3 system in acetonitrile, giving the more
satisfying results, was retained. Thus methyl esters of 6-bromo
veratric acid 16 and piperonic acid 17 were converted to the cor-
responding boronates in 77% yields and 55% yields, respectively.9,10
PdCl2(dppf)
The PdCl2(PPh3)2/NaHCO3 system giving the better results (en-
try 6), was retained for the elaboration of the other series. Un-
fortunately, extension to the three other series gave disappointing
results. Pd complex/base system effects were re-evaluated with the
other substrates and PdCl2(dppf)/K2CO3 association showed the
best compromise, leading to the different series of heteroaryl-aryl
compounds in a range of 50% yields (Scheme 4).13
CH3CN, Δ
O
B
R1
R2
Br
R1
R2
O
COOMe
NaHCO3,
Pinacol borane
COOMe
16: R1 = R2 = OCH3
17: R1, R2 = OCH2O
10: R1 = R2 = OCH3, 55%
11: R1, R2 = OCH2O, 77%
Scheme 3. Preparation of boronates 16 and 17.
N
N
O
O
O
O
O
B
2.1. Suzuki–Miyaura cross-coupling: creation of the
C10a–C10b bond
NO2
CO2Me
NO2
CO2Me
O
O
O
COOMe
19, 54%
20, 52%
10
At this stage a Suzuki–Miyaura reaction was planned to realize
the biaryl connection.5 Several reaction conditions were examined
with boronic esters 11 and quinoline 8 and results are summarized
in Table 1.11
Different solvents were considered. Acetonitrile gave the best
results and was consequently employed for further investigations.
Three palladium complexes, PdCl2(dppf), PdCl2(PPh3)2 and
Pd(PPh3)4, were selected. Also, the influence of the base was in-
vestigated. The same bases were used in these experiments, thus
8
9
PdCl2(dppf), K2CO3, CH3CN
microwaves
O
N
N
B
O
O
O
O
O
O
O
COOMe
11
NO2
CO2Me
NO2
CO2Me
18, 46%
21, 51%
Scheme 4. Summary of the Suzuki–Miyaura reaction.

C. Gene`s et al. / Tetrahedron 65 (2009) 10009–10015
10011
Moreover, microwave irradiation proved to be useful on the
experimental aspect permitting to dramatically decrease the initial
reaction time of 18 h to 1 h in the four series with the same yields.
interactions.15 At first, three dialkylaminoalkyl residues were se-
lected for their biological effectiveness in related series, thus con-
ducting to the preparation of 12 compounds (Table 3).16 The
objective here is to show the feasibility of our synthetic route for
a medicinal chemistry approach.
2.2. Ring C closure
Introduction of the desired aminoalkyl residues was performed
by treating the BZP with NaI, NaH and the corresponding dia-
lkylaminoalkylchloride in DMF (Table 3).17 After careful chroma-
tography, the corresponding substituted compounds were isolated
in low to moderate yields.
Access to the tetracycles was envisioned through nitro reduction
followed by spontaneous cyclization. Reducing agents such as SnCl2
and catalytic hydrogenation were envisaged.14 Various reactivities
were observed in the different series and results are summarized in
Table 2.
3. Conclusion
Table 2
Ring C closure
We disclosed here a versatile synthetic route to access new and
functionalized benzo[c]phenanthrolinones. The BZP skeleton was
thus prepared in only three steps in 22% yields for the dimethoxy-
substituted series and 32% for the methylenedioxy-substituted series.
The envisaged intermolecular Suzuki–Miyaura reaction to construct
the aryl-(iso)quinoline connections proved to be more reliable in
these series than the intramolecular cyclization. This methodology
permitted the access to a small library of 12 compounds for which the
biological applicability, mainly the DNA Topoisomerase I inhibition
and the cytotoxicity are currently under investigation.
Entry
Product
Yielda
H2/Ni Raneyb
SnCl2
47%
c
N
O
O
1
4
77%
NH
O
N
O
2
3
5
6
78%
55%
NH
NH
O
O
O
N
4. Experimental
O
O
33%
90%
4.1. General informations
N
All reactions were carried out in a dried glassware under an
argon atmosphere. All solvents were purchased with an analytical
grade from SDS. CH2Cl2 was distilled from CaH2. Methanol, aceto-
nitrile and DMF were dried over molecular sieves. PdCl2(dppf)
complex was purchased from Alfa Aesar. All other commercially
available reagents were used as-received. Yield refers to chroma-
tography and spectroscopically pure compounds, unless otherwise
noted. 1H NMR and 13C NMR spectra were recorded on a BRUCKER
AC 300 MHz spectrometer or a BRUCKER AVANCE 400 MHz spec-
trometer. Chemical shifts are reported in ppm and corrected to dH
7.26 and dC 77.16 for CDCl3 as internal reference. Coupling constants
(J) are given in Hertz. Mass spectra were measured with a ZQ 2000
Waters mass spectrometer (ESI). High resolution mass spectra were
obtained on a Q-ToF ESI mass spectrometer (Waters). Infra-red
spectra were recorded on a Nicolet FTIR spectrometer. Microwave
reactions were carried out on a Biotage apparatus (InitiatorÔ 2.0).
O
O
4
7
36%
83%
NH
O
a
isolated yields.
b
c
Reaction conditions: cat Ni Raney (5 equiv), H2 (5 bar), EtOH, rt for 48 h.
Reaction conditions: SnCl2.2H2O (5 equiv), MeOH, reflux for 48 h.
Results can be divided into two groups according to the sub-
stitution pattern on cycle D, i.e., dimethoxy (entries 1 and 2) and
methylenedioxy (entries 3 and 4). In the dimethoxy series (entries
1 and 2), good yields in tetracycle are obtained with catalytic hy-
drogenation, whereas moderate yields are attained with SnCl2.
In the methylenedioxy series (entries 3 and 4) reverse outcomes
are observed, SnCl2 offering thus the best alternative. The main
drawback in this step is the low solubility of the tetracycles, which
severely hinders the purification process after the catalytic reduction.
2.3. Introduction of dialkylaminoalkyl side chains
4.2. Experimental details and spectroscopic data
Having now the different tetracycles in hand, introduction of an
alkylaminoalkyl side chain can be envisaged. This structural mod-
ification is currently used in particular to increase DNA
4.2.1. 5-Nitro-6-hydroxyquinoline (13). To a solution of concen-
trated H2SO4 (40 mL) was slowlyadded 6-hydroxyquinoline 12 (6.0 g,
41.4 mmol). After 5 min, solid KNO3 (4.38 g, 43.5 mmol, 1.05 equiv)
Table 3
N-substituted benzo[c]phenanthrolinones
Y
Z
Y
NaH, NaI
DMF,
Y = N, Z = CH or Y = CH, Z = N
R1 = R2 = OCH3 or R1, R2 = OCH2O
Z
R1
R2
R1
R2
N
R
NH
R-Cl
Cl
Cl
N
O
Cl
N
R-Cl:
N
O
,
,
Entry
Amino Chain
Yielda,b
R1]R2]OCH3, Y]CH, Z]N
R1]R2]OCH3, Y]N, Z]CH
R1, R2]OCH2O, Y]CH, Z]N
R1, R2]OCH2O, Y]N, Z]CH
1
2
3
NCH2CH2N(CH3)2
NCH2CH2N(C2H5)2
NCH2CH2CH2N(CH3)2
22, 49%
23, 48%
24, 5%
25, 23%
26, 35%
27, 13%
28, 14%
29, 22%
30, 13%
31, 17%
32, 17%
33, 6%
a
Isolated yields.
b
Reaction conditions: NaI (1.5 equiv), R–Cl (1.1 equiv), NaH (3 equiv), DMF 110 ꢀC for 3 h.

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C. Gene`s et al. / Tetrahedron 65 (2009) 10009–10015
was added and the reaction mixture was stirred at 0 ꢀC for 2 h, then
poured into 400 g of crushed ice. pH was brought to 8–9 value using
a 33% NH4OH solution. The precipitate was filtered to give the title
compound as a green solid (6.24 g, 79% yield). IR (CH2Cl2, cmꢁ1) 3393,
2912, 2843, 2357, 2342, 1630,1526,1499, 1395,1322,1275, 1034, 977,
for 2 h, then poured into 400 g of crushed ice. pH was brought to 8–
9 value using a 33% NH4OH solution. The precipitate was filtered to
give the title compound 9 as a yellow solid (7.95 g, 95% yield). IR
(CH2Cl2, cmꢁ1) 3054, 2863, 1618, 1560, 1479, 1452, 1400, 1362, 1343,
1269, 1217, 1201, 1121, 1017, 932, 879, 824; 1H NMR (300 MHz,
877, 804; 1H NMR (300 MHz, CDCl3)
d
12.14 (SE, 1H), 9.26 (dd, J¼8.9,
CDCl3)
d
9.37 (d, J¼0.9 Hz, 1H), 8.73 (d, J¼6.1 Hz, 1H), 8.02 (dd,
1.4 Hz,1H), 8.88 (dd, J¼4.3,1.4 Hz,1H), 8.29 (d, J¼9.4 Hz,1H), 7.63 (dd,
J¼8.8, 0.8 Hz, 1H), 7.85 (d, J¼8.8 Hz, 1H), 7.54 (td, J¼6.1, 0.9, 0.8 Hz,
J¼8.9, 4.3 Hz, 1H), 7.51 (d, J¼9.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
1H); 13C NMR (75 MHz, CDCl3)
d 152.4, 146.3 (2C), 131.3, 131.1, 128.6,
d
158.5,149.0,143.4,140.6,131.6,127.0,124.7,123.1 (2C); MS (ESþ) m/z
127.1, 116.8, 113.8; MS (ESþ) m/z 253, 255 [MþH]þ; HRMS (ESþ) m/z
191 [MþH]þ; HRMS (ESþ) m/z calcd for C9H7N2O3 [MþH]þ 191.0457,
calcd for C9H6BrN2O2 [MþH]þ 252.9613, found 252.9609; UV lmax
found 191.0451; UV lmax (nm) (log
3) (CH2Cl2) 222 (3.88), 229 (4.06),
(nm) (log 3) (CH2Cl2) 222 (4.22), 232 (4.45).
320 (3.68), 373 (3.56).
4.2.5. 2-Bromo-4,5-dimethoxybenzoic acid methyl ester (16). A solu-
tion of 2-bromoveratric acid (10.0 g, 38.3 mmol) in methanol
(150 mL) was refluxed for 24 h in the presence of a catalytic amount
of concentrated sulfuric acid (1.5 mL). After disappearance of the
starting material, the solution was cooled to rt and concentrated
under reduced pressure. The residue was poured into water and
extracted by CH2Cl2. The organic layers were dried over MgSO4, fil-
tered and concentrated under vacuum to afford the title ester 16 as
a solid (7.48 g, 71% yield). IR (CH2Cl2, cmꢁ1) 3579, 3385, 3003, 2936,
2833, 1725, 1596, 1509, 1431, 1370, 1344, 1261, 1206, 1172, 1115, 1023,
4.2.2. 5-Nitro-6-trifluoromethanesulfonic quinoline (8). To a solution
of 5-nitro-6-hydroxyquinoline 13 (1.0 g, 5.3 mmol) in CH2Cl2
(25 mL), were successively added dried pyridine (850 mL, 10.6 mmol,
2 equiv) and freshly distilled triflic anhydride (1.3 mL, 7.95 mmol,
1.5 equiv). After disappearance of the starting material (TLC moni-
toring), water (30 mL) was added to the reaction mixture. Aqueous
and organic layers were separated and the aqueous layer was
washed with CH2Cl2 (3ꢂ30 mL). The combined organic layers were
dried over MgSO4, filtered and concentrated under vacuum. The
crude was purified by flash chromatography on silica gel (30% v/v
ethyl acetate/cyclohexane) to provide the desired compound 8 as
a pale yellow solid (1.4 g, 80% yield). IR (CH2Cl2, cmꢁ1) 3090, 3032,
2873, 1625, 1600, 1540, 1497, 1434, 1349, 1327, 1221, 1192, 1135, 1043,
986, 920, 866, 831, 810, 771; 1H NMR (300 MHz, CDCl3)
d 7.43 (s, 1H),
7.11 (s, 1H) 3.93 (s, 3H), 3.92 (s, 6H); 13C NMR (75 MHz, CDCl3)
d
165.9, 152.0, 147.8, 122.9, 116.9, 114.2, 114.0, 56.3, 56.2, 52.3; MS
(ESþ) m/z 297 [MþNa]þ; UV lmax (nm) (log
3) (CH2Cl2) 214 (3.55),
1
1022, 963, 879, 840, 825, 795, 768, 701; H NMR (300 MHz, CDCl3)
222 (4.15), 231 (4.35), 296 (3.59). Spectroscopic data were identical
d
9.13 (dd, J¼4.0, 1.3 Hz, 1H), 8.44 (d, J¼9.4 Hz, 1H), 8.32 (dd, J¼8.8,
to reported data.8
1.3 Hz, 1H), 7.80 (d, J¼9.4 Hz, 1H), 7.70 (dd, J¼8.8, 4.0 Hz, 1H) 13C
NMR (75 MHz, CDCl3)
d
152.9, 146.2, 138.4, 135.5, 131.0, 124.5, 122.7,
4.2.6. 2-bromo-4,5-methylenedioxybenzoic acid methyl ester (17). A
solution of 6-bromopiperonic acid (10.0 g, 40.8 mmol) in methanol
(150 mL) was refluxed for 24 h in presence of a catalytic amount of
concentrated sulfuric acid (1.5 mL). After disappearance of the
starting material, the solution was cooled to rt and concentrated
under reduced pressure. The residue was poured into water and
extracted by CH2Cl2. The organic layers were dried over MgSO4,
filtered and concentrated under vacuum to afford the title ester 17
as a solid (7.61 g, 72% yield). IR (CH2Cl2, cmꢁ1) 3003, 2960, 2914,
1728, 1614, 1505, 1496, 1437, 1383, 1354, 1248, 1184, 1140, 1087,
121.0, 120.6, 116.3; MS (ESþ) m/z 323 [MþH]þ; HRMS (ESþ) m/z calcd
for C10H5F3N2O5S [MþH]þ 322.9950, found 322.9947; UV lmax (nm)
(log 3) (CH2Cl2) 216 (3.85), 222 (3.87), 229 (4.23), 317 (3.52).
4.2.3. 6-Bromoisoquinoline (15). Aminoacetaldehyde diethylacetal
(12.4 mL, 85.6 mmol, 1.02 equiv) was added to a solution of 4-bro-
mobenzaldehyde 14 (15.54 g, 84 mmol) in toluene (100 mL). The
mixture was refluxed in a Dean Stark apparatus to remove water.
After 3 h, toluene was removed under reduced pressure. The residue
was dissolved in chlorobenzene (200 mL) and the solution was
cooled to ꢁ10 ꢀC. After dropwise addition of ethyl chloroformate
(8.17 mL, 85 mmol, 1.01 equiv), stirring was continued at ꢁ10 ꢀC
under N2 for 10 min. Trimethylphosphite (11.9 mL, 101 mmol,
1.2 equiv) was added, and the resulting mixture was warmed to rt
and stirred under N2 for 40 h. Then, the solution was cooled to 0 ꢀC
and TiCl4 (54 mL, 286 mmol, 3.4 equiv) was slowly added. The re-
action mixture was stirred at 100 ꢀC under N2 for 24 h. After cooling
to rt, the mixture wasdiluted with ethyl acetate and basified in an ice-
water bath using a 5 M aqueous NaOH solution. The product was
extracted with a mixture of ethyl acetate and hexanes (1:2, v/v). The
organic layer wasextracted with a 1 M aqueous HCl solution and after
separation the aqueous layer was basified to pH>10 with a 5 M
aqueous NaOH solution and extracted with CH2Cl2. The organic layer
was dried over Na2SO4 filtered and concentrated under reduced
pressure to give the expected compound 15 as a pale yellow solid
1033, 990, 935, 914, 867, 844, 773; 1H NMR (300 MHz, CDCl3)
d 7.37
(s, 1H), 7.14 (s, 1H), 6.10 (s, 2H), 3.94 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 165.6, 150.9, 147.1, 124.3, 114.9, 114.3, 110.9, 102.6, 52.3; MS
(ESþ) m/z 281 [MþNa]þ; U.V. lmax (nm) (log
3) (CH2Cl2) 222 (3.88),
232 (4.07), 266 (3.74), 301 (3.61). Spectroscopic data were identical
to reported data: Keck, G. E.; McLaws, M. D.; Wager, T. T. Tetrahedron
2000, 56, 9875.
4.2.7. 2-pinacolborane-4,5-dimethoxybenzoic acid methyl ester
(10). 2-bromo-4,5-dimethoxybenzoic acid methyl ester 16 (330 mg,
1.2 mmol), NaHCO3 (312 mg, 3.36 mmol, 3 equiv) and PdCl2(dppf)
(101 mg, 10% mol) were added in a round-bottom flask and purged
with a cycle vacuum-Argon flushing (3 x). Dried and degazed CH3CN
(5 mL) was added and the resulting mixture was stirred for one min.
Pinacolborane (540 mL, 3.6 mmol, 3 equiv) was then slowly added
and the deep-red solution was stirred at 120 ꢀC (oil bath) for 1 h. The
mixture was then cooled to rt, diluted with CH2Cl2 (5 mL) and
washed with H2O (1ꢂ10 mL). The aqueous layer was extracted with
CH2Cl2 (2ꢂ10 mL) and the combined organic phases were dried over
MgSO4, filtered and concentrated under reduced pressure. The
resulting dark-brown residue was purified by column chromatog-
raphy on silica gel (10% v/v ethyl acetate/cyclohexane) to give the
desired boronate 10 (212 mg, 55% yield) and the de-halogenated 4,5-
methylenedioxybenzoic acid methyl ester (102 mg, 43% yield). IR
(CH2Cl2, cmꢁ1) 3395, 2916, 2851, 1653, 1560, 1440, 1271, 1075, 1042,
(6.60 g, 38% yield). 1H NMR (300 MHz, CDCl3)
d 9.24 (s, 1H), 8.55 (d,
J¼5.8 Hz, 1H), 8.01 (d, J¼1.7 Hz, 1H), 7.84 (d, J¼8.7 Hz, 1H), 7.68 (dd,
J¼8.7, 1.7 Hz, 1H), 7.57 (d, J¼5.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
152.4, 144.0, 136.8, 130.9, 129.3, 128.8, 127.0, 125.2, 119.4; MS (ESþ)
m/z 208 [MþH]þ. Spectroscopic data were identical to data collected
from a commercial sample.
4.2.4. 5-Nitro-6-bromoisoquinoline (9). To a solution of concen-
trated H2SO4 (40 mL) was slowly added 6-bromoisoquinoline 15
(6.6 g, 31.5 mmol). After 5 min, solid KNO3 (3.35 g, 33.1 mmol,
1.05 equiv) was added and the reaction mixture was stirred at 0 ꢀC
879; 1H NMR (300 MHz, CDCl3)
3H), 3.91 (s, 3H), 3.89 (s, 3H), 1.42 (s, 12H); 13C NMR (75 MHz, CDCl3)
d 7.45 (s, 1H), 6.90 (s, 1H), 3.94 (s,

C. Gene`s et al. / Tetrahedron 65 (2009) 10009–10015
10013
d
167.9, 151.9, 149.0, 126.2 (2C), 113.7, 111.5, 83.8 (2C), 55.8 (2C), 52.0,
151.8, 151.5, 148.8, 147.0, 145.5, 133.8, 131.6, 131.2, 131.1, 130.7, 123.3,
121.5, 120.1, 113.2, 112.9, 56.2 (2C), 52.1; MS (ESþ) m/z 369 [MþH]þ;
HRMS (ESþ) m/z calcd for C19H16N2O6Na [MþNa]þ 391.0906, found
24.8 (4C); MS (ESþ) m/z 345 [MþNa]þ; HRMS (ESþ) m/z calcd for
C16H23O6Na [MþNa]þ 345.1485, found 345.1469; U.V. lmax (nm)
(log
3) (CH2Cl2) 229 (4.3), 267 (4.1), 288 (3.9).
391.0921; UV lmax (nm) (log 3) (CH2Cl2) 241 (4.1).
4.2.8. 2-pinacolborane-4,5-methylenedioxybenzoic acid methyl ester
(11). 6-bromo-2,3-methylenedioxybenzoic acid methyl ester 17
(500 mg, 1.93 mmol), NaHCO3 (487 mg, 5.8 mmol, 3 equiv) and
PdCl2(dppf) (155 mg, 10% mol) were added in a round-bottom flask
and purged with a cycle vacuum-Argon flushing (3 x). Dried and
degazed CH3CN (5 mL) was added and the resulting mixture was
4.3.3. 2-(5-Nitroisoquinolin-6-yl)-4,5-dimethoxybenzoic acid methyl
ester (20). (78 mg, 52% yield) IR (CH2Cl2, cmꢁ1) 3584, 3405, 2949,
2843, 1718, 1630, 1524, 1434, 1400, 1354, 1270, 1208, 1169, 1112,
1065, 1043, 995, 836, 773; 1H NMR (300 MHz, CDCl3)
d 9.37 (s, 1H),
8.68 (d, J¼6.1 Hz, 1H), 8.13 (d, J¼8.4 Hz, 1H), 7.65 (d, J¼6.1 Hz, 1H),
7.62 (s, 1H), 7.53 (d, J¼8.4 Hz, 1H), 6.75 (s, 1H), 3.98 (s, 3H), 3.89 (s,
stirred for one min. Pinacolborane (850
mL, 5.8 mmol, 3 equiv) was
3H), 3.65 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 165.9, 152.4, 151.9,
then slowly added and the deep-red solution was stirred at 120 ꢀC
(oil-bath) for 1 h. The mixture was then cooled to rt, diluted with
CH2Cl2 (5 mL) and washed with H2O (1ꢂ10 mL). The aqueous layer
was extracted with CH2Cl2 (2ꢂ10 mL) and the combined organic
phases were dried over MgSO4, filtered and concentrated under
reduced pressure. The resulting dark-brown residue was purified
by column chromatography on silica gel (10% v/v ethyl acetate/cy-
clohexane) to give the desired boronate 11 (456 mg, 77% yield) and
the de-halogenated 4,5-methylenedioxybenzoic acid methyl ester
(59 mg, 17% yield). IR (CH2Cl2, cmꢁ1) 2977, 2953, 1713, 1610, 1507,
1489, 1427, 1376, 1314, 1268, 1214, 1130, 1094, 1038, 964, 858, 786,
148.9, 145.6, 144.8, 137.8, 130.9, 129.6, 129.4, 127.5 (2C), 121.3, 114.7,
113.2, 112.5, 56.2 (2C), 52.1; MS (ESþ) m/z 369 [MþH]þ; HRMS (ESþ)
m/z calcd for C19H16N2O6Na [MþNa]þ 391.0906, found 391.0889;
UV lmax (nm) (log 3) (CH2Cl2) 222 (4.58), 232 (4.67).
4.3.4. 2-(5-Nitroisoquinolin-6-yl)-4,5-methylenedioxybenzoic acid
methyl ester (21). (90 mg, 51% yield) IR (CH2Cl2, cmꢁ1) 3390, 2911,
2850, 1713, 1625, 1527, 1500, 1430, 1369, 1261, 1130, 1086, 1032,
923, 782; 1H NMR (300 MHz, CDCl3)
d
9.40 (s,1H), 8.71 (d, J¼5.9 Hz,
1H), 8.15 (d, J¼8.5 Hz, 1H), 7.70 (d, J¼5.9 Hz, 1H), 7.55 (d, J¼8.5 Hz,
1H), 7.53 (s,1H), 6.74 (s,1H), 6.13 (dd, J¼4.1,1.1 Hz, 2H), 3.66 (s, 3H);
709, 669, 611; 1H NMR (300 MHz, CDCl3)
d
7.38 (s, 1H), 6.87 (s, 1H),
13C NMR (75 MHz, CDCl3)
d 165.5, 152.1, 150.9, 148.4, 145.1, 144.7,
6.00 (s, 2H), 3.87 (s, 3H), 1.40 (s, 12H); 13C NMR (75 MHz, CDCl3)
138.0, 132.7, 129.9, 129.4, 127.7 (2C), 123.0, 115.1, 110.7, 110.1, 102.6,
52.2; MS (ESþ) m/z 353 [MþH]þ, 416 [MþCH3CNþNa]þ; HRMS
(ESþ) m/z calcd for C18H12N2O6Na [MþNa]þ 375.0593, found
d
167.7, 151.0, 148.3, 127.5 (2C), 111.3, 109.1, 101.7, 83.9 (2C), 52.3,
24.8 (4C); MS (ESþ) m/z 329 [MþNa]þ; UV lmax (nm) (log
3)
(CH2Cl2) 222 (3.56), 230 (3.99), 269 (3.77), 298 (3.71). Spectroscopic
375.0587; UV lmax (nm) (log 3) (CH2Cl2) 235 (4.8), 272 (4.3), 297
data were identical to reported data.8
(4.1), 304 (3.7).
4.3. Heteroaryl-aryl formation: typical procedure
4.4. Nitro reduction and cyclization: typical procedures
In a microwave vial were successively added boronate ester 10 or
11 (0.65 mmol or 0.62 mmol, 1.5 equiv), 5-nitro-6-trifluoro-
methanesulfonic quinoline 8 or 5-nitro-6-bromoisoquinoline 9
(0.43 or 0.41 mmol), K2CO3 (1.29 or 1.23 mmol, 3 equiv) and
PdCl2(dppf) complex (0.043 or 0.041 mmol, 10% mol). The vial was
closed and subjected to a vacuum/Argon flushing cycle (3ꢂ). Then
degazed acetonitrile (5 mL) was added and the reaction mixture
was stirred for 1 h at 120 ꢀC under microwave irradiation. The
mixture was cooled to rt, diluted with water and extracted with
CH2Cl2. The organic layers were dried over MgSO4, filtered and
concentrated under vacuum. The remaining dark-brown oil was
purified by flash chromatography on silica gel (40% v/v ethyl acetate/
cyclohexane) to afford the corresponding biaryl.
4.4.1. Method 1: Reducing agent SnCl2. To a solution of biaryl
(200 mg, 0.54 mmol or 0.57 mmol) in methanol (150 mL) was
added SnCl2 (5 equiv) and the reaction mixture was refluxed under
argon for 48 h. Then the solvent was removed under reduced
pressure and the residue was poured into a 28% ammonia solution.
The precipitate formed was filtered, washed with CH2Cl2 and dried.
This material was then used without any further purification.
4.4.2. Method 2: hydrogenation. A stainless steel autoclave was
charged with
a solution of biaryl (200 mg, 0.54 mmol or
0.57 mmol) in methanol (150 mL). After addition of Raney Ni
(5 equiv), the autoclave was pressurized with H2 (5 bar) for 48 h.
The autoclave was then ventiled and the resulting mixture was
filtered, washed with DMF and concentrated in vacuo. The residue
was washed with CH2Cl2. The product was used without any fur-
ther purification.
4.3.1. 2-(5-Nitroquinolin-6-yl)-4,5-methylenedioxybenzoic acid methyl
ester (18). (70 mg, 46% yield) IR (CH2Cl2, cmꢁ1) 2949, 2922, 2844,
1722, 1614, 1526, 1504, 1486, 1436, 1376, 1254, 1131, 1084, 1037, 925,
839, 812, 796; 1H NMR (300 MHz, CDCl3)
d
9.02 (dd, J¼4.2, 1.6 Hz,
1H), 8.26 (dd, J¼8.7, 0.8 Hz, 1H), 8.18 (ddd, J¼8.7, 1.6, 0.8 Hz, 1H), 7.59
(d, J¼8.7 Hz, 1H), 7.56 (dd, J¼8.7, 4.2 Hz, 1H), 7.55 (s, 1H), 6.75 (s, 1H),
6.10 (dd, J¼4.5, 1.2 Hz, 2H), 3.62 (s, 3H); 13C NMR (75 MHz, CDCl3)
4.4.3. 8,9-Dimethoxybenzo[c][1,7]phenanthrolin-6-one (4). Method
1: 78 mg, 47% yield Method 2: 127 mg, 77% yield IR (KBr, cmꢁ1
)
2360, 1648, 1494, 1373, 1272, 1125, 865; (ESþ) m/z 307 [MþH]þ.
d
165.6,151.6, 150.8,148.2,147.1, 145.3, 133.7,132.9,131.9, 130.9,130.7,
123.4, 123.2, 120.1, 110.6, 110.4, 102.5, 52.1; MS (ESþ) m/z 376
[MþNa]þ; HRMS (ESþ) m/z calcd for C18H12N206Na [MþNa]þ
4.4.4. 8,9-Dimethoxybenzo[c][1,8]phenanthrolin-6-one (5). Method
1: 91 mg, 55% yield Method 2: 129 mg, 78% yield IR (KBr, cmꢁ1
)
375.0593, found 375.0610; UV lmax (nm) (log
3) (CH2Cl2) 222 (4.48),
1664; 1652; 1645; 1610; 1524; 1385; 1285; 1090; (ESþ) m/z 307
[MþH]þ.
231 (4.68).
4.3.2. 2-(5-Nitroquinolin-6-yl)-4,5-dimethoxybenzoic acid methyl
ester (19). (81 mg, 54% yield) IR (CH2Cl2, cmꢁ1) 3371, 2951, 2919,
2851, 1717, 1600, 1526, 1493, 1434, 1355, 1277, 1207, 1174, 1111, 1057,
4.4.5. 8,9-Methylenedioxybenzo[c][1,7]phenanthrolin-6-one (6).
Method 1: 149 mg, 90% yield Method 2: 55 mg, 33% yield IR (KBr,
cmꢁ1) 3393, 3124, 3031, 2906, 1653, 1626, 1605, 1529, 1499, 1402,
1351, 1262, 1199, 1035; (ESþ) m/z 291 [MþH]þ.
881, 775; 1H NMR (300 MHz, CDCl3)
d
8.99 (dd, J¼4.2, 1.5 Hz, 1H),
8.25 (dd, J¼8.6, 1.5 Hz, 1H), 8.15 (d, J¼8.6 Hz, 1H), 7.64 (s, 1H), 7.61
(d, J¼8.6 Hz, 1H), 7.54 (dd, J¼8.6, 4.2 Hz, 1H), 6.76 (s, 1H), 3.97 (s,
4.4.6. 8,9-Methylenedioxybenzo[c][1,8]phenanthrolin-6-one (7).
Method 1: 130 mg, 83% yield Method 2: 60 mg, 36% yield IR (KBr,
3H), 3.88 (s, 3H), 3.63 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
166.0,

10014
C. Gene`s et al. / Tetrahedron 65 (2009) 10009–10015
cmꢁ1) 3419, 3185, 3030, 2917,1655,1615,1495,1444,1410,1271,1252,
cmꢁ1) 3370, 2943, 1614, 1592, 1525, 1496, 1463, 1426, 1416, 1328,
1272, 1208, 1179, 1116, 1059, 1031, 1001, 820, 758; 1H NMR
1025; (ESþ) m/z 291 [MþH]þ.
(300 MHz, CDCl3)
d
9.45 (dd, J¼8.1, 1.8 Hz, 1H), 8.99 (dd, J¼4.1,
4.5. Introduction of dialkylaminoalkyl side chains: general
procedure
1.8 Hz, 1H), 8.53 (dd, J¼9.2, 1.8 Hz, 1H), 8.08 (d, J¼9.2 Hz, 1H), 7.85
(s, 1H), 7.74 (s, 1H), 7.56 (dd, J¼8.1, 4.1 Hz, 1H), 4.91 (t, J¼6.0 Hz,
2H), 4.14 (s, 3H), 4.10 (s, 3H), 2.99 (t, J¼6.0 Hz, 2H), 2.46 (s, 6H); 13C
At 0 ꢀC, to a solution of a benzo[c]phenanthrolin-6-one (80 mg),
NaI (1.5 equiv) and the appropriate dialkylaminoalkylchloride hy-
drochloride (1.1 equiv) in DMF (20 mL) was added NaH (60% min-
eral oil suspension, 3 equiv) in small portions over 5 min. The
mixture was allowed to warm to rt with stirring for 45 min. Then
the flask was transferred into a preheated oil bath (65 ꢀC), and
heated at 110 ꢀC for 3 h. After disappearance of the starting material
(TLC monitoring), the mixture was cooled to rt and quenched by
addition of a few drops of water. The solvent was removed under
vacuum and the crude product was dissolved in 1 M aqueous HCl
solution (50 mL). The aqueous layer was washed with CH2Cl2
(3ꢂ50 mL), basified with a 30% aqueous NaOH solution and
extracted with CH2Cl2 (6ꢂ75 mL). The organic layers were com-
bined, dried over MgSO4 and concentrated under vacuum. The
NMR (75 MHz, CDCl3) d 158.1, 152.9, 150.3, 149.7, 148.6, 138.8,
133.0, 130.6, 126.6, 125.4, 123.5, 121.2, 118.2, 114.4, 104.5, 102.2,
64.4, 58.2, 56.1 (2C), 46.2 (2C); MS (ESþ) m/z 378 [MþH]þ; HRMS
(ESþ) m/z calcd for C22H24N3O3 [MþH]þ 378.1818, found 378.1818;
UV lmax (nm) (log 3) (CH2Cl2) 222 (4.68), 282 (4.98), 338 (3.98),
353 (3.65).
4.5.5. 5-[20-(Diethylamino)ethyl]-8,9-dimethoxybenzo[c][1,7]-
phenanthrolin-6(5H)-one (26). (37 mg, 35% yield) IR (CH2Cl2,
cmꢁ1) 3381, 2966, 2925, 1659, 1592, 1524, 1428, 1272, 1116, 1087,
1060, 1037, 786; 1H NMR (300 MHz, CDCl3)
d
9.47 (dd, J¼8.4,
1.5 Hz, 1H), 9.00 (dd, J¼4.3, 1.5 Hz, 1H), 8.55 (d, J¼9.3 Hz, 1H),
8.09 (d, J¼9.3 Hz, 1H), 7.86 (s, 1H), 7.74 (s, 1H), 7.59 (dd, J¼8.4,
4.3 Hz, 1H), 4.95 (t, J¼6.1 Hz, 2H), 4.17 (s, 3H), 4.10 (s, 3H), 3.21 (t,
J¼6.1 Hz, 2H), 2.86 (q, J¼7.2 Hz, 2ꢂ2H), 1.23 (t, J¼7.2 Hz, 2ꢂ3H);
residue was purified by chromatography on silica gel (20/45
CH2Cl2/MeOH/NH4OH 95/4.35/0.65 v/v/v).
m,
13C NMR (75 MHz, CDCl3)
d 158.1, 153.0, 150.3, 149.8, 148.6, 138.8,
133.0, 130.6, 126.6, 125.5, 123.6, 121.2, 118.2, 114.4, 104.4, 102.2,
64.4, 56.1 (2C), 51.2, 48.1 (2C), 11.9 (2C); MS (ESþ) m/z 405
[MþH]þ; HRMS (ESþ) m/z calcd for C24H28N3O3 [MþH]þ 406.2131,
4.5.1. 5-[20-(Dimethylamino)ethyl]-8,9-dimethoxybenzo[c][1,8]-
phenanthrolin-6(5H)-one (22). (48 mg, 49% yield) IR (CH2Cl2, cmꢁ1
)
3403, 2934, 2854, 2778, 2356, 2343, 1731, 1645, 1615, 1591, 1523,
found 406.2126; UV lmax (nm) (log 3) (CH2Cl2) 222 (4.4), 282
1486, 1455, 1417, 1329, 1274, 1209, 1035, 835, 789, 757, 723; 1H NMR
(4.6).
(300 MHz, CDCl3)
d
9.29 (s, 1H), 8.84 (d, J¼5.6 Hz, 1H), 8.72 (d,
J¼5.6 Hz, 1H), 8.32 (d, J¼8.9 Hz, 1H), 7.85 (d, J¼8.9 Hz, 1H), 7.77 (s,
4.5.6. 5-[30-(Dimethylamino)propyl]-8,9-dimethoxybenzo[c][1,7]-
phenanthrolin-6(5H)-one (27). (13 mg, 13% yield) IR (CH2Cl2,
cmꢁ1) 3369, 2944, 1660, 1614, 1592, 1525, 1496, 1428, 1415, 1332,
1272, 1208, 1178, 1059, 1037, 820, 788; 1H NMR (300 MHz, CDCl3)
1H), 7.72 (s, 1H), 4.91 (t, J¼5.9 Hz, 2H), 4.14 (s, 3H), 4.10 (s, 3H), 3.01
(t, J¼5.9 Hz, 2H), 2.50 (s, 2ꢂ3H); 13C NMR (75 MHz, CDCl3)
d 157.9,
153.0, 151.3, 150.3, 144.2, 137.7, 135.0, 130.4, 128.0, 122.9, 121.4,
120.9, 117.4, 115.1, 104.6, 102.4, 63.7, 57.8, 56.3, 56.2, 45.8 (2C); MS
(ESþ) m/z 378 [MþH]þ; HRMS (ESþ) m/z calcd for C22H24N3O3
d
9.47 (ddd, J¼8.3, 1.8, 0.7 Hz, 1H), 8.99 (d, J¼4.3, 1.8 Hz, 1H), 8.53
(d, J¼9.2 Hz, 1H), 8.08 (dd, J¼9.2, 0.7 Hz, 1H), 7.84 (s, 1H), 7.72 (s,
1H), 7.58 (d, J¼8.3, 4.3 Hz, 1H), 4.84 (t, J¼6.5 Hz, 2H), 4.16 (s, 3H),
4.10 (s, 3H), 2.63 (t, J¼7.4 Hz, 2H), 2.35 (s, 2ꢂ3H), 2.27–2.20 (m,
[MþH]þ 378.1818, found 378.1807; UV lmax (nm) (log
3) (CH2Cl2)
212 (3.89), 222 (4.26), 229 (4.33), 281 (4.68), 342 (3.65), 359 (3.59).
2H); 13C NMR (75 MHz, CDCl3)
d 158.3, 152.9, 150.3, 149.8, 148.6,
4.5.2. 5-[20-(Diethylamino)ethyl]-8,9-dimethoxybenzo[c][1,8]-
138.9, 133.1, 130.6, 126.6, 125.3, 123.6, 121.1, 118.1, 114.5, 104.3,
102.2, 64.6, 56.9, 56.1 (2C), 45.6 (2C), 27.4; MS (ESþ) m/z 392
[MþH]þ; HRMS (ESþ) m/z calcd for C23H26N3O3 [MþH]þ 392.1974,
phenanthrolin-6(5H)-one (23). (50 mg, 48% yield) IR (CH2Cl2, cmꢁ1
)
3379, 2957, 2921, 2851, 1731, 1714,1592,1523,1455,1423,1329,1273,
1209, 1162, 1121, 1092, 1037, 789; 1H NMR (300 MHz, CDCl3)
d
9.24 (s,
found 392.1978; UV lmax (nm) (log 3) (CH2Cl2) 222 (4.5), 282
1H), 8.83 (d, J¼5.8 Hz, 1H), 8.66 (d, J¼5.8 Hz, 1H), 8.33 (d, J¼9.1 Hz,
1H), 7.85 (d, J¼9.1 Hz, 1H), 7.77 (s, 1H), 7.71 (s, 1H), 4.93 (t, J¼6.0 Hz,
2H), 4.13 (s, 3H), 4.07 (s, 3H), 3.22 (t, J¼6.0 Hz, 2H), 2.86 (q, J¼7.2 Hz,
(4.7).
4.5.7. 5-[20-(Dimethylamino)ethyl]-8,9-methylenedioxybenzo[c][1,8]-
phenanthrolin-6(5H)-one (28). (14 mg, 14% yield) IR (CH2Cl2, cmꢁ1
3363, 2911, 2845, 2763, 1620, 1576, 1489, 1467, 1260, 1195, 1032, 939,
836, 759; 1H NMR (300 MHz, CDCl3)
2ꢂ2H), 1.21 (t, J¼7.2 Hz, 2ꢂ3H); 13C NMR (75 MHz, CDCl3)
d
157.8,
)
152.9, 151.0, 150.3, 143.7, 137.5, 135.0, 130.3, 128.0, 122.7, 121.5, 121.0,
117.6, 115.0, 104.4, 102.4, 63.5, 56.2, 56.1, 50.9, 47.9 (2C), 11.2 (2C); MS
(ESþ) m/z 405 [MþH]þ; HRMS (ESþ) m/z calcd for C24H28N3O3
d
9.30 (s, 1H), 8.87 (d, J¼5.7 Hz,
1H), 8.74 (d, J¼5.7 Hz, 1H), 8.31 (d, J¼9.0 Hz, 1H), 7.87 (d, J¼9.0 Hz,
1H), 7.86 (s,1H), 7.76 (s,1H), 6.18 (s, 2H), 4.91 (t, J¼5.8 Hz, 2H), 2.99 (t,
[MþH]þ 406.2131, found 406.2112; UV lmax (nm) (log
3) (CH2Cl2) 214
(3.8), 222 (4.3), 229 (4.3), 281 (4.6), 342 (3.6), 359 (3.5).
J¼5.8 Hz, 2H), 2.48 (s, 2ꢂ3H); 13C NMR (75 MHz, CDCl3)
d 158.3, 151.6,
151.3, 148.6, 144.2, 137.9, 135.0, 132.2, 128.1, 122.8, 121.5, 121.2, 117.5,
116.5, 102.7, 102.0, 100.4, 64.5, 58.2, 46.1 (2C); MS (ESþ) m/z 362
[MþH]þ; HRMS (ESþ) m/z calcd for C21H20N3O3 [MþH]þ 362.1505,
4.5.3. 5-[30-(Dimethylamino)propyl]-8,9-dimethoxybenzo[c][1,8]-
phenanthrolin-6(5H)-one (24). (5 mg, 5% yield) IR (CH2Cl2, cmꢁ1
)
3400, 2915, 1646, 1615, 1591, 1523, 1485, 1448, 1426, 1275, 1093,
found 362.1487; UV lmax (nm) (log 3) (CH2Cl2) 281 (4.6), 342 (3.4),
1034; 1H NMR (300 MHz, CDCl3)
d
9.25 (s, 1H), 8.83 (d, J¼5.8 Hz, 1H),
360 (3.4).
8.66 (d, J¼5.8 Hz, 1H), 8.36 (d, J¼9.0 Hz, 1H), 7.90 (d, J¼9.0 Hz, 1H),
7.80 (s,1H), 7.70 (s,1H), 4.84 (t, J¼6.2 Hz, 2H), 4.14 (s, 3H), 4.11 (s, 3H),
3.02 (t, J¼7.5 Hz, 2H), 2.63 (s, 2ꢂ3H), 2.48–2.40 (m, 2H); 13C NMR
4.5.8. 5-[20-(Diethylamino)ethyl]-8,9-methylenedioxybenzo[c][1,8]-
phenanthrolin-6(5H)-one (29). (24 mg, 22% yield) IR (CH2Cl2, cmꢁ1
3385, 2917, 2840, 1620, 1587, 1470, 1328, 1263, 1195, 1129, 1035; 1H
NMR (300 MHz, CDCl3)
)
(75 MHz, CDCl3)
d 157.8, 153.1, 151.0, 150.4, 143.6, 137.4, 135.1, 130.3,
128.0,122.8,121.6,121.1,117.6,115.0,104.3,102.4, 63.6, 56.6, 56.2 (2C),
d
9.31 (s, 1H), 8.89 (d, J¼5.7 Hz, 1H), 8.74 (d,
44.2 (2C), 25.7; MS (ESþ) m/z 392 [MþH]þ; HRMS (ESþ) m/z calcd for
J¼5.7 Hz, 1H), 8.32 (d, J¼9.0 Hz, 1H), 7.90 (d, J¼9.0 Hz, 1H), 7.89 (s,
1H), 7.75 (s, 1H), 6.20 (s, 2H), 4.89 (t, J¼6.3 Hz, 2H), 3.13 (t, J¼6.3 Hz,
2H), 2.79 (q, J¼7.1 Hz, 2ꢂ2H), 1.18 (t, J¼7.1 Hz, 2ꢂ3H); 13C NMR
C23H26N3O3 [MþH]þ 392.1974, found 392.1983; UV lmax (nm) (log
3)
(CH2Cl2) 196 (3.7), 222 (4.1), 229 (4.1), 281 (4.4), 361 (3.4).
(75 MHz, CDCl3) d 158.2, 151.7, 151.3, 148.7, 144.3, 138.0, 135.0, 132.4,
4.5.4. 5-[20-(Dimethylamino)ethyl]-8,9-dimethoxybenzo[c][1,7]-
phenanthrolin-6(5H)-one (25). (23 mg, 23% yield) IR (CH2Cl2,
128.1, 123.0, 121.6, 121.2, 117.5, 116.6, 102.6, 102.1, 100.6, 64.7, 51.2,
48.0 (2C), 11.8 (2C); MS (ESþ) m/z 390 [MþH]þ; HRMS (ESþ) m/z

C. Gene`s et al. / Tetrahedron 65 (2009) 10009–10015
10015
calcd for C23H24N3O3 [MþH]þ 390.1818, found 390.1815; UV lmax
376 [MþH]þ; HRMS (ESþ) m/z calcd for C22H22N3O3 [MþH]þ 376.1661,
(nm) (log
3
) (CH2Cl2) 219 (4.3), 222 (4.3), 228 (4.0), 281 (4.3).
found 376.1657; UV lmax (nm) (log 3) (CH2Cl2) 214 (3.9), 222 (4.3), 232
(4.2), 282 (4.5).
4.5.9. 5-[30-(Dimethylamino)propyl]-8,9-methylenedioxybenzo[c][1,8]-
phenanthrolin-6(5H)-one (30). (14 mg, 13% yield) IR (CH2Cl2, cmꢁ1
3386, 2946, 2911, 2816, 2764,1625,1585,1493,1470,1455,1332,1261,
1233, 1197, 1036, 838, 763; 1H NMR (300 MHz, CDCl3)
9.30 (s, 1H),
)
Acknowledgements
d
Elise Prost and Pascale Leproux (UMR CNRS 8638) are gratefully
acknowledged for their excellent technical assistance (NMR and
Mass spectrometry). We thank ARC for a fellowship for C.G.
8.88 (d, J¼5.7 Hz, 1H), 8.74 (d, J¼5.7 Hz, 1H), 8.31 (d, J¼9.0 Hz, 1H),
7.88 (d, J¼9.0 Hz, 1H), 7.86 (s, 1H), 7.74 (s, 1H), 6.19 (s, 2H), 4.82 (t,
J¼6.4 Hz, 2H), 2.62 (t, J¼7.1 Hz, 2H), 2.35 (s, 6H), 2.19 (td, J¼7.1, 6.4 Hz,
2H); 13C NMR (75 MHz, CDCl3)
d 158.4,151.5,151.3,148.6,144.2,138.0,
Supplementary data
135.0, 132.2, 128.1, 122.7, 121.5, 121.1, 117.5, 116.6, 102.5, 102.0, 100.5,
64.8, 56.8, 45.6 (2C), 27.4; MS (ESþ) m/z 376 [MþH]þ; HRMS (ESþ) m/z
calcd for C22H22N3O3 [MþH]þ 376.1661, found 376.1659; UV lmax
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2009.09.110.
(nm) (log
362 (3.5).
3)(CH2Cl2) 215 (4.0), 222 (4.6), 230 (4.3), 281 (4.7), 343 (3.6),
References and notes
4.5.10. 5-[20-(Dimethylamino)ethyl]-8,9-methylenedioxybenzo[c][1,7]-
1. (a) Suffness, M.; Cordell, G. A. The Alkaloids; Academic: 1985; 25; 178; (b) Simanek,
V. The Alkaloids; Academic: 1985; 26; 185.
2. Pommier, Y. Nat. Rev. Cancer 2006, 6, 789; Pommier, Y. Chem. Rev. 2009, 109,
2894.
phenanthrolin-6(5H)-one (31). (17 mg, 17% yield) IR (CH2Cl2, cmꢁ1
)
1
3371, 2915, 2854, 2357, 2342, 1658, 1478, 1457, 1257, 1031; H NMR
(300 MHz, CDCl3)
d
9.46 (dd, J¼8.4,1.4 Hz,1H), 9.00 (dd, J¼4.3,1.4 Hz,
3. Prado, S.; Michel, S.; Tillequin, F.; Koch, M. J. Heterocycl. Chem. 2006, 43, 1261.
4. For early discussions on this strategy in natural phenanthridinone series see:
Only one example reported in the natural benzophenanthridine series, see:
Geen, G. R.; Mann, I. S.; Mullane, M. V.; McKillop, A. Tetrahedron 1998, 54, 9875;
Banwell, M. G.; Cowden, C. J. Aust. J. Chem. 1994, 47, 2235; Yang, Y.; Ho¨rnfeldt,
A.-B.; Gronowitz, S. J. Heterocycl. Chem. 1989, 26, 865; Siddiqui, M. A.; Snieckus,
V. Tetrahedron Lett. 1988, 29, 5463.
1H), 8.48 (d, J¼9.3 Hz, 1H), 8.07 (d, J¼9.3 Hz, 1H), 7.90 (s, 1H), 7.77 (s,
1H), 7.57 (dd, J¼8.4, 4.3 Hz, 1H), 6.19 (s, 2H), 4.92 (t, J¼5.9 Hz, 2H),
3.00 (t, J¼5.9 Hz, 2H), 2.48 (s, 2ꢂ3H); 13C NMR (75 MHz, CDCl3)
d
158.3, 151.6, 150.5, 148.7, 148.2, 139.0, 133.0, 132.6, 126.5, 125.6,
123.7, 121.2, 118.6, 115.8, 102.6, 102.0, 100.3, 64.3, 58.1, 46.0 (2C); MS
5. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633.
(ESþ) m/z 362 [MþH]þ; HRMS (ESþ) m/z calcd for C21H20N3O3
[MþH]þ 362.1505, found 362.1492; UV lmax (nm) (log
3) (CH2Cl2)
6. Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478.
7. For a synthesis from bromo indene see: Sit, S.-Y.; Xie, K.; Jacutin-Porte, S.; Boy,
K. M.; Seanz, J.; Taber, M. T.; Gulwadi, A. G.; Korpinen, C. D.; Burris, K. D.; Molski,
T. F.; Ryan, E.; Xu, C.; Verdoorn, T.; Johnson, G.; Nichols, D. E.; Mailman, R. B.
Bioorg. Med. Chem. 2004, 12, 715; Miller, R. B.; Frincke, J. M. J. Org. Chem. 1980,
45, 5312.
8. Mentzel, U. V.; Tanner, D.; Tonder, J. E. J. Org. Chem. 2006, 71, 5807.
9. Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem. 2000, 65, 164.
10. Introduction of boronic residue by deprotonation or halogen-lithium exchange
gave similar results. See Naumov, M. I.; Sutirin, S. A.; Shavyrin, A. S.; Ganina, O. G.;
Beletskaya, I. P.; Bourgarel-Rey, V.; Combes, S.; Finet, J.-P.; Fedorov, A. Y. J. Org.
Chem. 2007, 72, 3293.
222 (4.2), 239 (4.2), 281 (4.6).
4.5.11. 5-[20-(Diethylamino)ethyl]-8,9-methylenedioxybenzo[c][1,7]-
phenanthrolin-6(5H)-one (32). (19 mg, 17% yield) IR (CH2Cl2, cmꢁ1
)
3379, 2959, 2910, 2845, 2355, 2333, 1603, 1527, 1467, 1440, 1325,
1293, 1255, 1184, 1124, 1032, 934, 825; 1H NMR (300 MHz, CDCl3)
d
9.44 (dd, J¼8.3, 1.5 Hz, 1H), 9.00 (dd, J¼4.3, 1.5 Hz, 1H), 8.43 (d,
J¼9.2 Hz, 1H), 8.05 (d, J¼9.2 Hz, 1H), 7.85 (s, 1H), 7.70 (s, 1H), 7.57
(dd, J¼8.3, 4.3 Hz, 1H), 6.18 (s, 2H), 4.88 (t, J¼6.2 Hz, 2H), 3.14 (t,
J¼6.2 Hz 2H), 2.80 (q, J¼7.1 Hz, 2ꢂ2H), 1.18 (t, J¼7.1 Hz, 2ꢂ3H); 13C
11. 6-OH quinoline 12 has been involved in Pd-catalyzed cross coupling reactions.
See: Arnould, J. C.; Didelot, M.; Cadilhac, C.; Pasquet, M. J. Tetrahedron Lett. 1996,
26, 4523; Aulenta, F.; Reissig, H.-U. Synlett 2006, 2993; So, C. M.; Lee, H. W.; Lau,
C. P.; Kwong, F. Y. Org. Lett. 2009, 11, 317.
NMR (75 MHz, CDCl3) d 158.2, 151.5, 150.4, 148.7, 148.1, 138.9, 133.0,
132.5, 126.5, 125.6, 123.6, 121.1, 118.5, 115.7, 102.4, 101.9, 100.2, 64.4,
51.3, 48.0 (2C),11.9 (2C); MS (ESþ) m/z 390 [MþH]þ; HRMS (ESþ) m/z
calcd for C23H23N3O3Na [MþNa]þ 412.1637, found 412.1656; UV lmax
12. 5-nitro-6-hydroxy quinoline 13 is the main observed by-product of the
reaction. In some cases dimer boronate formation is observed too.
13. These conditions were also applied to the synthesis of boronates 10 and 11 and
furnished the corresponding de-halogenated compounds limiting thus the
development of a one-step sequence.
(nm) (log 3) (CH2Cl2) 239 (4.5), 282 (4.7).
14. Craig, J. J.; Cass, W. E. J. Am. Chem. Soc. 1942, 64, 783; Li, J. H.; Serdyuk, L.;
Ferraris, D. V.; Xiao, G.; Tays, K. L.; Kletzly, P. W.; Li, W.; Lautar, S.; Zhang, J.;
Kalish, V. J. Bioorg. Med. Chem. Lett. 2001, 11, 1687; Ling, C.; Lahti, P. M. J. Am.
Chem. Soc. 1994, 116, 8784.
15. Janin, Y. L.; Croisy, A.; Riou, J.-F.; Bisagni, E. J. Med. Chem.1993, 36, 3686; Nagarajan,
M.; Morrell, A.; Fort, B. C.; Meckley, M. R.; Antony, S.; Kohlhagen, G.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2004, 47, 5651.
16. Li, T.-K.; Houghton, P. J.; Desai, S. D.; Daroui, P.; Liu, A. A.; Hars, E. S.; Ruchelman,
A. L.; LaVoie, E. J.; Liu, L. F. Cancer Res. 2003, 63, 8400; Ruchelman, A. L.; Singh,
S. K.; Wu, X.; Ray, A.; Yang, J.-M.; Li, T.-K.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg.
Med. Chem. Lett. 2002, 12, 3333.
17. Zhu, S.; Ruchelman, A. L.; Zhou, N.; Liu, A. A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med.
Chem. 2005, 13, 6782.
4.5.12. 5-[30-(Dimethylamino)propyl]-8,9-methylenedioxybenzo[c][1,7]-
phenanthrolin-6(5H)-one(33). (6 mg, 6% yield) IR (CH2Cl2, cmꢁ1) 3374,
2916, 2845, 1606, 1470, 1447, 1250, 1135, 1035; 1H NMR (300 MHz,
CDCl3)
d
9.48 (dd, J¼8.3,1.4 Hz,1H), 9.01 (dd, J¼4.3,1.4 Hz,1H), 8.48 (d,
J¼9.2 Hz, 1H), 8.08 (d, J¼9.2 Hz, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.59 (dd,
J¼8.3, 4.3 Hz, 1H), 6.20 (s, 2H), 4.84 (t, J¼6.3 Hz, 2H), 2.74 (t, J¼7.6 Hz,
2H), 2.43 (s, 2ꢂ3H), 2.28 (qu, J¼2H); 13C NMR (75 MHz, CDCl3)
d 158.3,
151.6, 150.5, 148.7, 148.2, 139.0, 133.1, 132.6, 126.5, 125.6, 123.7, 121.2,
118.6, 115.7, 102.4, 102.0, 100.3, 64.3, 56.7, 45.1, 26.8 (2C); MS (ESþ) m/z