A new entry to phenanthridine ring systems via sequential application of Suzuki and the modified Pictet-Spengler reactions

Article abstract of DOI:10.1039/b905696c

A mild, efficient and versatile method has been developed for the two step synthesis of phenanthridine ring systems using the Suzuki and the modified Pictet-Spengler strategy. The strategy involves synthesis of a substrate in which an aryl amine is tether

Full text of DOI:10.1039/b905696c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A new entry to phenanthridine ring systems via sequential application of
Suzuki and the modified Pictet–Spengler reactions†
Anil K. Mandadapu, Mohammad Saifuddin, Piyush K. Agarwal and Bijoy Kundu*
Received 20th March 2009, Accepted 9th April 2009
First published as an Advance Article on the web 22nd May 2009
DOI: 10.1039/b905696c
A mild, efficient and versatile method has been developed for the two step synthesis of phenanthridine
ring systems using the Suzuki and the modified Pictet–Spengler strategy. The strategy involves synthesis
of a substrate in which an aryl amine is tethered to an activated arene ring at the carbon ortho to the
activated carbon nucleophile so as to facilitate the formation of phenanthridine ring via p-cyclization.
satile and straightforward synthesis methods for phenanthridine
Introduction
ring systems with diverse physical and chemical properties has
The phenanthridine is a common pharmacophore present in
remained target of continuous investigation.5 While traditional
a wide variety of naturally occurring phenanthridine and ben-
protocols relied extensively on Bischler–Napieralski cyclization
zophenanthridine alkaloids. Among them nitidine (Fig. 1) and
methods,6 strategies involving metal catalyzed reaction has been
other benzo[c]phenanthridine alkaloid analogues1 exhibit potent
also described. Hulme and co-workers7 applied Pd-catalyzed
anti-tumor activity by the inhibition of DNA topoisomerase
intramolecular Heck cyclization for the robust synthesis of
I,2 and are considered as potential anti-tumor drugs.3 However,
phenanthridines. Similarly, nickel or palladium catalyzed iminoan-
due to their isolation in poor yields and association with broad
nulation of an internal alkyne has been used as a method to syn-
range of anti-infectious activities,4 search for more efficient, ver-
thesize benzo[c]phenanthridines.8 Other methods for the synthesis
of phenanthridines and benzophenanthridines include either
intramolecular ortho-arylation of aryl amide ions with aryl halides
via SRN1 reactions9 or Stille coupling of nitroarylstannanes
with o-bromobenzaldehyde.10 Shabashov and Daugulis reported
trifluoroacetic anhydride promoted formation of phenanthridines
from ortho-arylated anilides.11 A one-pot reaction involving aro-
matic aldehydes, anilines and benzenediazonium-2-carboxylate
has been reported for the synthesis of 6-aryl-phenanthridines
via a cascade process.12 However, the above reported strategies
remain associated with certain disadvantages such as stringent
and harsh reaction conditions, use of metal catalysts or poor
generality/limited diversity.
In view of our interest in pursuing SAR studies pertaining to
their anti-tumor activities, we applied the recently introduced
modified Pictet–Spengler strategy13 reported by us with the
possibility of synthesizing a diverse library based upon the
phenanthridine-pharmacophore. The approach involves conden-
Fig. 1 Structures of benzo[c]phenanthridine alkaloids.
sation of activated heterocycle-linked aryl amine substrates with
Division of Medicinal and Process Chemistry, Central Drug Research Insti-
aldehydes/ketones to furnish polycyclic structures via p (6-endo)-
cyclization. Interestingly, our approach based on an activated
heterocycle holds significance towards the synthesis of phenanthri-
dine rings since all the phenanthridine-based biologically active
alkaloids in general have activating group(s) as substitution in
the ring A (Fig. 2). In this report we describe a new entry to the
tute, Lucknow 226001, India. E-mail: bijoy_kundu@yahoo.com; Fax: +91-
0522-2223405, 2223938. CDRI Communication No. 7748; Tel: +91-0522-
2212411-18, ext 4383
† Electronic supplementary information (ESI) available: Compound char-
acterization data of 2b, 2e, 2g, 6l-w, 7d–f, 8h-p and copies of 1H NMR
and 13C NMR spectra of compounds 6a–w, 7a–f, and 8a–p. See DOI:
10.1039/b905696c
Fig. 2 Retrosynthetic analysis of phenanthridines based on the modified Pictet–Spengler strategy.
2796 | Org. Biomol. Chem., 2009, 7, 2796–2803 This journal is The Royal Society of Chemistry 2009
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Table 1 Optimization of the reaction conditions for conversion of
substrate 2a to 6a
efficient synthesis of complex building block phenanthridines from
commercially available starting materials.
Retrosynthetic analysis (Fig. 2) based on the modified Pictet–
Spengler strategy suggests that phenanthridines could be obtained
by condensing carbonyl compounds with the activated arene-
linked aryl amine substrates via 6-endo trig cyclization. The most
interesting feature of the strategy is the introduction of diversity
at C-6 of the phenanthridine ring since reports dealing with the
synthesis of 6-substituted-phenanthridines are scarce.12,14
Reaction
Conditions
Entry
Temp/◦C
Time
Yield of 6aa
1.
2.
3.
4.
5.
2% TFA in DCM
1% p-TsOH in ACN
1% TFA in toluene
2% TFA in ACN
2% TFA in toluene
rt
12 h
12 h
12 h
12 h
12 h
29
30
35
30
65
Reflux
Reflux
Reflux
Reflux
a Isolated yield.
Result and discussion
4a-d used for Suzuki couplings were obtained from commer-
cial sources, 5a-b were synthesized from 1-amino naphthalene
using the published procedures.17 For the Pictet–Spengler cy-
clization (Scheme 2), the substrate 2a was initially treated with
4-chlorobenzaldehyde under the traditional Pictet–Spengler pro-
tocols involving 2% TFA in DCM at both 0 ◦C and at room
temperature. However, these resultedinthe isolationofthecyclized
product in >20% yield. This led us to carry out cyclization under
other acidic conditions involving 1% p-TsOH in acetonitrile, 1%
TFA in toluene, 2% TFA in toluene and 2% TFA in acetonitrile.
The presence of 2% TFA in toluene effected complete conversion
of 2a and afforded 6a in >85% purity based on HPLC (Table 1).
The crude product obtained after workup was purified by silica
gel column chromatography using EtOAc/hexane as an eluent
and was isolated in 65% yield. The low recovery of the compound
from column chromatography can be attributed to the basic
nature of the compound which was evident from the fact that
after reeluting the column with neat EtOAc, the remaining
material was recovered albiet in >90% purity. Changing column
chromatography packings from silica gel to alumina did not
improve the isolated yields. The phenanthridine derivative 6a
was characterized using NMR and ESMS. As reported earlier
by us,13a,c,e,g the p-cyclization of the imine 1 occurred via the
formation of a dihydro derivative in the first instance, followed
by spontaneous air oxidation. The strategy was then extended
to the formation of benzophenanthridine rings by condensing
substrate 2f with 4-chlorobenzaldehyde in 2% TFA in toluene
under reflux. As expected the reaction led to the formation of
benzophenanthridine 8a via p-cyclization. Next, we examined the
scope and limitation of the strategy by extending the strategy
to six additional variously substituted aryl amine substrates: 2b,
The key step in our synthesis strategy involves synthesis of
a substrate 2a (Scheme 1) in which an aryl amine (ring B)
is tethered to an activated arene ring A at the carbon ortho
to the activated carbon nucleophile so as to facilitate the for-
mation of a phenanthridine ring via a ring closure involving
p-cyclization (Scheme 1). The synthesis of 2a was affected in
one step by condensing 3,4-dimethoxyphenylboronic acid 3a
with 2-bromo aniline 4a via Suzuki reaction without protecting
the amino functionality in 82% isolated yield. Surprisingly,
reports on Pd-catalyzed Suzuki reactions involving free aryl
amines are scarce.15 We then successfully applied this strat-
egy to the synthesis of seven additional substrates 2b-h us-
ing three phenyl boronic acids 3a-c and six 2-halo-arylamines
4a-d and 5a-b with isolated yields of substrates ranging from 65–
82%. Synthesis of substrates 2a, 2b, 2c 2e, 2f and 2g were carried
out from commercially available 3,4-dimethoxyphenylboronic
acid 3a whereas for the synthesis of substrates 2d and 2h,
the required boronic derivatives 2-(3,5-dimethyl-phenyl)-4,4,5,5-
tetramethyl-[1,3,2]dioxaborolane 3b and 4,4,5,5-tetramethyl-2-
(3,4,5-trimethyl-phenyl)-[1,3,2]dioxaborolane 3c were obtained
from their corresponding phenolic derivatives using the published
procedure.16 Similarly, while the 2-halo aryl amines derivatives
Scheme 1 General strategies for the synthesis of substrates 2a-h.
Scheme 2 A general strategy for the modified Pictet–Spengler reaction.
Org. Biomol. Chem., 2009, 7, 2796–2803 | 2797
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Table 2 Endo cyclized products phenanthridines resulting from the condensation of substrates 2a-h and R8CHO
Entry
Substrate
R8
Product
Yield (%)
tR/mina
1.
2.
3.
4.
5.
6.
7.
8.
9.
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2c
2d
2d
2d
2d
2e
2e
2e
2e
2e
2e
2f
4-Cl-C6H4
4-NO2-C6H4
4-Br-C6H4
6a
6b
6c
6d
6e
6f
6g
6h
6i
65
60
58
48
45
50
52
59
55
58
60
54
49
66
60
59
61
56
60
53
55
54
56
61
60
59
65
58
56
62
59
60
57
65
61
66
75
65
62
63
64
61
63
60
59
20.70
20.32
20.32
18.80
17.27
18.65
20.15
22.77
20.20
24.94
22.43
22.80
22.40
25.09
24.83
21.91
23.78
24.57
25.51
21.45
21.55
21.16
21.09
18.48
22.64
20.23
19.13
21.34
23.62
22.10
21.14
20.46
19.18
21.53
21.12
22.55
21.79
20.49
22.26
20.78
21.34
21.46
19.48
20.56
21.23
4-F-C6H4
4-OH-C6H4
3,4-di-(OCH3)-C6H3
H
4-F-C6H4
4-CN-C6H4
3,4-di-Cl-C6H4
3,4-di-(OCH3)-C6H3
C6H5
4-Me-C6H4
4-Cl-C6H4
4-OEt-C6H4
3,4-di-(OCH3)-C6H3
4-F-C6H4
4-Me-C6H4
4-(CH3)2N-C6H4
4-Cl-C6H4
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
8g
8h
8i
3,4-di-(OCH3)-C6H3
4-OH-C6H4
4-NO2-C6H4
4-F-C6H4
4-Br-C6H4
4-(CH3)2N-C6H4
4-NO2-C6H4
4-OEt-C6H4
4-Me-C6H4
4-Cl-C6H4
4-OEt-C6H4
4-(CH3)2N-C6H4
4-OH-C6H4
4-NO2-C6H4
H
2f
2f
2f
2f
2g
2g
2g
2g
2g
2g
2g
2h
2h
2h
2h
4-Cl-C6H4
3,4-di-(OCH3)-C6H3
4-(CH3)2N-C6H4
4-Br-C6H4
4-OEt-C6H4
4-F-C6H4
8j
8k
8l
8m
8n
8o
8p
4-Cl-C6H4
3,4-di-(OCH3)-C6H3
4-NO2-C6H4
4-Br-C6H4
a Retention time on HPLC (C18 reversed-phase column; 150 ¥ 4.6 mm; 5 mm) with a linear gradient of 10–100% CH3CN in water over 30 min, flow rate
of 1.0 mL/min, and UV detection at 220/254 nm.
2c, 2d and 2e analogous to 2a, and 2g and 2h analogous to 2f.
In all cases the substrates efficiently underwent p-cyclization when
condensed with aromatic aldehydes to furnish the title compounds
in satisfactory yields (Table 2). The presence of electron-donating
and withdrawing group on aromatic aldehydes had no affect on
cyclization, however, aliphatic aldehydes with the exception of
formaldehyde and ketones failed to undergo 6-endo cyclization.
All endo cyclized products reported in Table 2 are new except for
compound 6g.18
phenanthridine core unit by promoting the p-cyclization in a wide
range of activated arene-linked aryl amine substrates.
Experimental
General
All solvents were commercially available and used without purifi-
1
cation. All products were characterized by HNMR, 13C NMR,
ESMS, HRMS, IR and HPLC. Analytical TLC was performed
using 2.5 ¥ 5 cm plated coated with a 0.25 mm thickness of silica
gel 60F-254 and visualization was accomplished with UV light
and iodine. Column chromatography was performed using silica
gel (100–200 mesh). 1H NMR spectra (300 MHz) and (200 MHz)
are reported as follows: chemical shifts in ppm downfield from
TMS as internal standard (d scale), multiplicity [bs = broad singlet,
Conclusion
In conclusion we have developed an efficient and versatile method
for the synthesis of phenanthridine rings using commercially
available reactants. Our modified Pictet–Spengler strategy allows
access to a three-point diversity library based upon the 6-aryl-
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s = singlet, d = doublet, t = triplet, q=quartet, m = multiplet, o =
overlapped, integration and coupling constant (Hz)]. All 13C NMR
spectra (75 MHz) and (50 MHz) are determined with complete
proton decoupling and reported in ppm. Analytical HPLC were
performed on a reverse phase C-18 column (250 mm ¥ 4.6 mm).
Retention times on HPLC (C18 reversed-phase column; 150 ¥
4.6 mm; 5 mm) with a linear gradient of 10–100% CH3CN in
water over 30 min, flow rate of 1.0 mL/min, and UV detection
at 220/254 nm. Mass spectra were recorded on a electron-spray
mass spectrometer.
chromatography on silica gel using hexane:ethyl acetate (v/v) as
the eluent to afford 2a. Yield = 0.53 g (80%), white solid, mp
114–116 ◦C, Rf = 0.46 (1:3 v/v ethylacetate/hexane), IR (KBr)
1
nmax 3458, 3371, 1625, 1515 cm-1; H NMR (200 MHz, CDCl3):
d = 7.18–7.10 (m, 2H, ArH), 7.03–6.92 (m, 3H, ArH), 6.85–6.74
(m, 2H, ArH), 3.68 (bs, 2H, NH2), 3.92 (s, 3H, OCH3), 3.89 (s,
3H, OCH3); 13C NMR (75 MHz, CDCl3): d = 149.1, 148.2, 143.7,
132.2, 130.5, 128.4, 127.6, 121.3, 118.7, 115.6, 112.4, 111.5, 56.05,
56.0; mass (ES+) m/z 230.2 (M+ + 1); Anal. Calcd for C14H15NO2:
C, 73.34; H, 6.59; N, 6.11; Found: C, 73.28; H, 6.64; N, 6.07.
Procedure for synthesis of 2-bromo-1-naphthylamine 5a. To a
solution of NBS (10.0 mmol) in DCM (80.0 mL) cooled to -78 ◦C
was added ZrCl4 (0.5 mmol), followed by 1-aminonaphthalene
(10.0 mmol) under nitrogen atmosphere. The reaction was carried
out for 1 h and then quenched by adding saturated NaHCO3
aq solution followed by extraction with CH2Cl2. The extracted
organic phase (CH2Cl2) was washed with brine and dried over
Na2SO4. The solvent was removed under pressure to give 2-bromo-
1-naphthylamine 5a. Yield = 74%, white solid, mp 73–76 ◦C, Rf =
3¢,4¢-Dimethoxy-4-(trifluoromethyl)[1,1¢-biphenyl]-2-amine 2c.
Yield = 0.48. g (75%), brown solid, mp 150–152 ◦C, Rf = 0.53
(1:6 v/v ethylacetate/hexane), IR (KBr) nmax 3452, 3019, 1626,
1
1504 cm-1; H NMR (300 MHz, CDCl3): d = 7.54–7.19 (m, 2H,
ArH), 7.11–6.95 (m, 4H, ArH), 3.93 (s, 3H, OCH3), 3.90 (s, 3H,
OCH3), 3.89 (bs, 2H, NH2); 13C NMR (50 MHz, CDCl3): d =
149.3, 148.8, 144.1, 130.7 (d, J = 8.5 Hz), 120.2 (d, J = 14.5 Hz),
115.0, 112.3, 111.9, 119.8, 111.7, 110.5, 105.9, 100.7, 56.6, 56.1;
mass (ES+) m/z 298.2 (M+ + 1); Anal. Calcd for C15H14F3NO2: C,
60.60; H, 4.75; N, 4.71; Found: C, 60.65; H, 4.70; N, 4.75.
1
0.59 (hexane), IR (KBr) nmax 3401, 3050, 1625, 1503 cm-1; H
NMR (200 MHz, CDCl3): 7.79–7.77 (m, 2H, ArH), 7.40 (d, 3H,
J = 8.1 Hz, ArH), 7.17 (d, 1H, J = 8.8 Hz, ArH), 4.63 (s, 2H, NH2);
13C NMR (75 MHz, CDCl3): d = 139.5, 133.2, 129.6, 128.4, 126.0,
125.6, 123.6, 121.1, 119.0, 103.9; mass (ES+) m/z 224.0 (M+ + 1);
Anal. Calcd for C10H8BrN: C, 54.08; H, 3.63; N, 6.31; Found: C,
54.05; H, 3.65; N, 6.33.
2-(3,4-Dimethoxyphenyl)naphthalen-1-amine 2f. Yield = 1.8 g
(80%), brown solid, mp 136–137 ◦C, Rf = 0.36 (1:50 v/v
ethylacetate/hexane), IR (KBr) nmax 3477, 3384, 3003, 2960, 1625,
1
1577 cm-1; H NMR (300 MHz, CDCl3): d = 7.89–7.80 (m, 2H,
ArH), 7.52–7.43 (m, 2H, ArH), 7.38–7.25 (m, 2H, ArH), 7.11–
6.91 (m, 3H, ArH), 3.81 (s, 2H, NH2), 3.94 (s, 3H, OCH3), 3.90 (s,
3H, OCH3); 13C NMR (50 MHz, CDCl3): d = 148.3, 138.5, 133.7,
132.7, 128.7, 128.6, 125.8, 125.4, 122.2, 121.9, 121.2, 118.6, 112.9,
111.7, 105.9, 100.7, 56.1; mass (ES+) m/z 280.2 (M+ + 1); Anal.
Calcd for C18H17NO2: C, 77.40; H, 6.13; N, 5.01; Found: C, 77.45;
H, 6.09; N, 5.00.
Procedure for synthesis of 2,4-dibromo-naphthalen-1-amine 5b.
The mixture of 1-aminonaphthalene (7 mmol) and sulfonic-
acid-functionalized silica (85 mg) in 1:3 CH3CN:Et2O (28 mL)
was treated with NBS (7.34 mmol). The mixture was stirred
at room temperature and the reaction was monitored by tlc.
After the completion of the reaction in 15 min, the mixture
was filtered. The filtrate was concentrated and the residue was
subjected to column chromatography on silica gel using (1:99 v/v)
ethylacetate/hexane to obtain pure 2,4-dibromo-naphthalen-1-
amine 5b. Yield = 70%, brown solid, mp 121–123 ◦C, Rf =
0.58 (1:99 v/v ethylacetate/hexane), IR (KBr) nmax 3427, 1633,
Precedure for synthesis of
2,4-bis(3,4,5-trimethylphenyl)naphthalen-1-amine 2h
A mixture of trifluoro-methanesulfonic acid 3,4,5-trimethyl-
phenyl ester19 (1.0 g, 3.7 mmol) and bis(neopentyl glyco-
lato)diboron (1.69 g, 7.5 mmol) and potassium acetate (1.1 g,
11.2 mmol) was treated with dimethyl sulfoxide (2 mL) and
degassed with nitrogen for 15 min followed by addition of
bis(pinacolato)diboron (0.31 g, 0.37 mmol) under continuous
flow of nitrogen. The reaction mixture was stirred at 80 ◦C for
1 h, followed by the addition of Cs2CO3 (1.5 ml, 3.7M). After
10 min, 2,4-dibromo-naphthalen-1-amine 5b (0.4 g, 1.4 mmol)
and Pd(PPh3)4 (0.43 g, 0.37 mmol) were added to the reaction
mixture under nitrogen atmosphere. The reaction mixture was
stirred at 80 ◦C for 2 h. After completion of the reaction, the
solution was filtered with celite, washed with EtOAc (5 mL) and
this filtrate was diluted with H2O (15 mL), and the resulting
product was extracted three times with EtOAc (20 mL). The
organic layer was washed with brine and dried over anhydrous
Na2SO4 followed by the removal of solvent in vacuo. The crude
product was purified by column chromatography on silica gel using
(1:50 v/v) ethylacetate/hexane as eluent to afford 2,4-bis(3,4,5-tri
methylphenyl) naphthalen-1-amine 2h. Yield = 0.38 g (65%), semi
solid, Rf = 0.52 (1:5 v/v ethylacetate/hexane), IR (KBr) nmax 3783,
1
1425 cm-1; H NMR (200 MHz, CDCl3): d = 8.20–8.15 (m, 1H,
ArH), 7.82–7.77 (m, 2H, ArH), 7.64–7.49 (m, 2H, ArH), 4.66 (bs,
2H, NH2); 13C NMR (50 MHz, CDCl3): d = 139.7, 132.7, 131.5,
128.1, 127.5, 126.6, 124.5, 121.5, 111.0, 103.5; mass (ES+) m/z
301.6 (M+ + 1); Anal. Calcd for C10H7Br2N: C, 39.91; H, 2.34; N,
4.65; Found: C, 39.96; H, 2.31; N, 4.61.
General procedure for the synthesis of substrates 2a-c and 2e-g via
Suzuki coupling
The solution of 2-bromoaniline 4a (1 equiv) in DMF (5 mL) was
degassed with nitrogen for 15 min followed by addition of Na2CO3
(5 mL, 2M) under continuous flow of nitrogen. After 10 min,
3,4-dimethoxyphenyl boronic acid 3a (1.2 equiv) and Pd(PPh3)4
(0.1 equiv) were added to the reaction mixture under a nitrogen
atmosphere. The reaction mixture was stirred at 80 ◦C for 1 h.
After completion of the reaction the solution was diluted with
H2O (15 mL), and then the product was extracted three times with
EtOAc (15 mL) and washed with brine. The combined organic
layer was dried over anhydrous Na2SO4 and the solvent was
removed in vacuo. The crude product was purified by column
1
3017, 2924, 1614, 1449 cm-1; H NMR (300 MHz, CDCl3): d =
7.98 (dd, 1H, J1 = 8.2 Hz, J2 = 23.5 Hz, ArH), 7.55–7.40 (m, 2H,
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ArH), 7.30–7.17 (m, 2H, ArH), 6.50 (s, 4H, ArH), 4.22 (bs, 2H,
NH2), 2.34 (s, 6H, 2 ¥ CH3), 2.22 (s, 12H, 4 ¥ CH3); 13C NMR
(50 MHz, CDCl3): d = 138.1 137.6, 137.2, 137.1, 136.8, 136.3,
134.1, 133.6, 131.6, 131.3, 130.5, 129.8, 129.6, 128.8, 126.9, 125.6,
125.2 125.1, 124.1, 122.3, 121.5, 114.5, 20.7, 15.4, 15.3, 14.6; mass
(ES+) m/z 380.5 (M+ + 1); Anal. Calcd for C28H29N: C, 88.61; H,
7.70; N, 3.69; Found: C, 88.63; H, 7.72; N, 3.65.
ethylacetate/hexane), IR (KBr) nmax 3021, 2925, 1613, 1517 cm-1;
1H NMR (300 MHz, CDCl3): d = 8.49–8.46 (m, 1H, ArH), 8.19
(dd, 1H, J1 = 1.4 Hz, J2 = 8.0 Hz, ArH), 7.98 (s, 1H, ArH), 7.73–
7.62. (m, 6H, ArH), 7.37 (s, 1H, ArH), 4.16 (s, 3H, OCH3), 3.88
(s, 3H, OCH3); 13C NMR (75 MHz, CDCl3): d = 158.4, 152.7,
149.6, 143.6, 139.2, 131.8, 131.3, 130.4, 129.4, 128.2, 126.8, 123.6,
123.1, 121.6, 120.2, 107.9; 102.3, 56.3, 56.1; mass (ES+) m/z 394.3
(M+ + 1); Anal. Calcd for C21H16BrNO2:C, 63.97; H, 4.09; N, 3.55;
Found: C, 63.93; H, 4.16; N, 3.58.
Procedure for synthesis of 3¢,5¢-dimethyl[1,1¢-biphenyl]-2-amine 2d
This was obtained in a similar manner to that described for
2h using trifluoro-methanesulfonic acid 3,5-dimethyl-phenyl ester
and 2,4-dibromo-naphthalen-1-amine 5b.
6-(4-Fluorophenyl)-8,9-dimethoxyphenanthridine 6d. Yield =
0.17 g (48%), white solid, mp 188–189 ◦C, Rf = 0.50 (1:4 v/v
ethylacetate/hexane), IR (KBr) nmax 3069, 2995, 1602, 1503 cm-1;
1H NMR (200 MHz, CDCl3): d = 8.49 (d, 1H, J = 7.38 Hz, ArH),
8.22 (d, 1H, J = 7.8 Hz, ArH), 7.98 (s, 1H, ArH), 7.77–7.64. (m,
4H, ArH), 7.38 (s, 1H, ArH), 7.29–7.23 (t, 2H, J = 9.57 Hz, ArH),
4.17 (s, 3H, OCH3), 3.88 (s, 3H, OCH3); 13C NMR (50 MHz,
CDCl3): d = 163.1 (d, J = 246.0 Hz), 158.6, 152.7, 149.5, 143.6,
136.7, 136.6, 131.5, 130.4, 129.5, 128.2, 126.7, 123.6, 121.6, 120.5,
115.6 (d, J = 21.5 Hz), 108.2, 102.3, 56.3, 56.0; mass (ES+) m/z
334.3 (M+ + 1); Anal. Calcd for C21H16FNO2: C, 75.66; H, 4.84;
N, 4.20; Found: C, 75.69; H, 4.88; N, 4.16.
Yield = 0.49 g (75%), liquid, Rf = 0.40 (1:25 v/v ethylac-
1
etate/hexane), IR (Neat) nmax 3420, 2920, 1608, 1492 cm-1; H
NMR (200 MHz, CDCl3): d = 7.13 (t, 1H, J = 1.8 Hz, ArH),
7.10–7.06 (m, 3H, ArH), 6.99 (d, 1H, J = 0.6 Hz, ArH), 6.84–
6.73 (m, 2H, ArH), 3.76 (bs, 2H, NH2), 2.36 (s, 6H, 2 ¥ CH3);
13C NMR (50 MHz, CDCl3): d = 143.6, 139.5, 138.5, 130.5, 128.9,
128.4, 128.1, 126.9, 122.5, 118.7, 115.6, 21.5; mass (ES+) m/z 198.2
(M+ + 1); Anal. Calcd for C14H15N: C, 85.24; H, 7.66; N, 7.10;
Found: C, 85.21; H, 7.64; N, 7.15.
General procedure for the Pictet–Spengler reaction leading to
the synthesis of phenanthridine derivatives 6, 7 and 8. A mixture
of 2 (1 equiv) and corresponding aldehyde R8 (1.2 equiv) was
treated with 2% solution of trifluoroactetic acid in toluene (5 mL).
The reaction mixture was refluxed overnight. After completion of
reaction, the toluene was evaporated in vacuo and the residue was
extracted with aq. NaHCO3 (20 mL) and EtOAc (3 ¥ 10 mL). The
combined organic layer was dried over anhydrous Na2SO4 and the
solvent was removed in vacuo. The crude product was purified on
silica gel column using ethylacetate/hexane (v/v) as eluent.
4-(8,9-Dimethoxyphenanthridin-6-yl)phenol 6e. Yield = 0.16 g
(45%), white solid, mp 248–250 ◦C, Rf = 0.20 (1:3 v/v ethylac-
1
etate/hexane), IR (KBr) nmax 3442, 1614, 1516 cm-1; H NMR
(200 MHz, DMSO-d6): d = 9.79 (s, 1H, OH), 8.80–8.76 (m, 1H,
ArH), 8.23 (s, 1H, ArH), 8.01 (dd, 1H, J1 = 1.7 Hz, J2 = 7.7 Hz
ArH), 7.71–7.60 (m, 4H, ArH), 7.50 (s, 1H, ArH), 6.96 (d, 2H,
J = 12.8, ArH), 4.09 (s, 3H, OCH3), 3.80 (s, 3H, OCH3); 13C
NMR (50 MHz, DMSO-d6): d = 159.1, 158.5, 152.9, 149.6, 143.4,
131.6, 130.8, 129.7, 129.3, 128.4, 126.6, 123.4, 123.1, 120.0, 115.6,
108.5, 103.6, 56.6, 55.8; mass (ES+) m/z 332.3 (M+ + 1); Anal.
Calcd for C21H17NO3: C, 76.12; H, 5.17; N, 4.23; Found: C, 76.15;
H, 5.21; N, 4.28.
6-(4-Chlorophenyl)-8,9-dimethoxyphenanthridine 6a. Yield =
0.19 g (65%), white solid, mp 178–180 ◦C, Rf = 0.56 (1:4 v/v
ethylacetate/hexane), IR (KBr) nmax 3096, 2923, 1616, 1522 cm-1;
1H NMR (200 MHz, CDCl3): d = 8.50–8.45 (m, 1H, ArH), 8.22–
8.17 (m, 1H, ArH), 7.98 (s, 1H, ArH), 7.74–7.64 (m, 4H, ArH),
7.57–7.52 (m, 2H, ArH), 7.37 (s, 1H, ArH), 4.16 (s, 3H, OCH3),
3.88 (s, 3H, OCH3); 13C NMR (50 MHz, CDCl3): d = 158.4, 152.7,
149.6, 143.5, 138.7, 134.9, 131.1, 130.5, 129.5, 128.8, 128.2, 126.8,
123.6, 121.6, 120.3, 108.0, 102.3, 56.3, 56.1; mass (ES+) m/z 350.3
(M+ + 1); Anal. Calcd for C21H16ClNO2: C, 72.10; H, 4.61; N, 4.00;
Found: C, 72.18; H, 4.66; N, 4.03.
6-(3,4-Dimethoxyphenyl)-8,9-dimethoxyphenanthridine
6f.
Yield = 0.20 g (50%), white solid, mp 173–175 ◦C, Rf = 0.25
(2:3 v/v ethylacetate/hexane), IR (KBr) nmax 3083, 3000, 2883,
1
1518 cm-1; H NMR (200 MHz, CDCl3): d = 8.49–8.45 (m, 1H,
ArH), 8.24–8.19 (m, 1H, ArH), 7.93 (s, 1H, ArH), 7.74–7.59. (m,
2H, ArH), 7.50 (s, 1H, ArH), 7.36–7.32 (m, 2H, ArH), 7.05 (d,
1H, J = 2.6 Hz, ArH), 4.16 (s, 3H, OCH3), 3.99 (s, 3H, OCH3),
3.96 (s, 3H, OCH3), 3.92 (s, 3H, OCH3); 13C NMR (50 MHz,
CDCl3): d = 159.3, 152.6, 149.7, 149.4, 149.2, 143.6, 132.9, 129.5,
128.0, 126.5, 123.5, 122.4, 121.6, 120.6, 113.0, 111.2, 108.6, 102.3,
56.2, 56.0; mass (ES+) m/z 376.3 (M+ + 1); Anal. Calcd for
C23H21NO4: C, 73.58; H, 5.64; N, 3.73; Found: C, 73.54; H, 5.69;
N, 3.77.
8,9-Dimethoxy-6-(4-nitrophenyl)phenanthridine 6b. Yield =
0.23 g (60%), yellow solid, mp 228–230 ◦C, Rf = 0.34 (1:3 v/v
ethylacetate/hexane), IR (KBr) nmax 3070, 3026, 1610, 1518,
1
1353 cm-1; H NMR (300 MHz, CDCl3): d = 8.52–8.49 (m, 1H,
ArH), 8.43 (d, 2H, J = 8.7 Hz, ArH), 8.21–8.18 (m, 1H, ArH),
8.01 (s, 1H, ArH), 7.95 (d, 2H, J = 8.8 Hz, ArH), 7.76–7.66 (m,
2H, ArH), 7.27 (s, 1H, ArH), 4.18 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3); 13C NMR (75 MHz, CDCl3): d = 157.2, 153.0, 149.9,
148.1, 146.9, 143.5, 130.8, 129.7, 128.5, 127.3, 123.9, 123.8, 121.8,
119.9, 107.4, 102.5, 56.4, 56.1; mass (ES+) m/z 360.2 (M+ + 1);
Molecular Formula: C21H16N2O4; MS (HR EI) m/z calcd for [M]+
360.111 found 360.1113.
8,9-Dimethoxy phenant◦hridine 6g. Yield = 0.13 g (52%), light
orange solid, mp 164–165 C [Lit18b 163–164 ◦C]; Rf = 0.32 (1:4 v/v
ethylacetate/hexane), IR (KBr) nmax 3068, 2942, 1609, 1508 cm-1;
1H NMR (300 MHz, CDCl3): d = 9.65 (s, 1H, ArH), 8.58–8.55
(m, 1H, ArH), 8.44–8.41 (m, 1H, ArH), 7.97 (s, 1H, ArH), 7.87–
7.85 (m, 2H, ArH), 7.55 (s, 1H, ArH), 4.25 (s, 3H, OCH3), 4.01 (s,
3H, OCH3); 13C NMR (50 MHz, CDCl3): d = 158.9, 152.1, 133.0,
132.6, 131.3, 129.9, 124.2, 122.9, 122.0, 119.6, 110.2, 102.3, 57.0,
56.6; mass (ES+) m/z 240.3 (M+ + 1); Anal. Calcd for C15H13NO2:
C, 75.30; H, 5.48; N, 5.85; Found: C, 75.36; H, 5.45; N, 5.82.
6-(4-Bromophenyl)-8,9-dimethoxyphenanthridine 6c. Yield =
0.24 g (58%), white solid, mp 193–195 ◦C, Rf = 0.66 (1:4 v/v
2800 | Org. Biomol. Chem., 2009, 7, 2796–2803
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6-(4-Fluorophenyl)-8,9-dimethoxy-2-methylphenanthridine 6h.
Yield = 0.21 g (59%), white solid, mp 195–197 ◦C, Rf = 0.36
(1:4 v/v ethylacetate/hexane), IR (KBr) nmax 3020, 2967, 1515,
4.21 (s, 3H, OCH3), 3.91 (s, 3H, OCH3); 13C NMR (75 MHz,
CDCl3): d = 163.3 (d, J = 247.5 Hz), 159.4, 153.0, 150.9, 149.0,
140.5, 138.3, 137.4, 136.0, 135.9, 131.5, 131.4, 130.6, 126.8, 123.4,
122.5, 115.7 (d, J = 21.0 Hz), 107.5, 103.5, 56.6, 56.1; mass (ES+)
m/z 335.3 (M+ + 1); Anal. Calcd for C20H15FN2O2: C, 71.85; H,
4.52; N, 8.38; Found: C, 71.81; H, 4.56; N, 8.35.
1
1216 cm-1; H NMR (200 MHz, CDCl3): d = 8.23 (s, 1H, ArH),
8.08 (d, 1H, J = 8.4 Hz ArH), 7.95 (s, 1H, ArH), 7.78–7.68. (m,
2H, ArH), 7.53 (dd, 1H, J1 = 1.7 Hz, J2 = 8.4 Hz, ArH), 7.36
(s, 1H, ArH), 7.29–7.20 (m, 2H, ArH), 4.18 (s, 3H, OCH3), 3.87
(s, 3H, OCH3), 2.65 (s, 3H, CH3); 13C NMR (50 MHz, CDCl3):
d = 163.1 (d, J = 246.0 Hz), 157.7, 152.4, 149.4, 141.9, 136.6,
136.5, 131.6, 131.4, 130.1, 130.0, 129.1, 123.4, 121.1, 120.5, 115.6
(d, J = 21.5 Hz), 108.0, 102.2, 56.3, 56.0, 22.1; mass (ES+) m/z
348.3 (M+ + 1); Anal. Calcd for C22H18FNO2: C, 76.06; H, 5.22;
N, 4.03; Found: C, 76.16; H, 5.25; N, 4.09.
6-(4-Bromophenyl)-8,9-dimethoxy-6a,10a-dihydrobenzo[c][1,5]-
naphthyridine7b. Yield = 0.20 g (60%), brown solid, mp 187–
189 ◦C, Rf = 0.42 (1:4 v/v ethylacetate/hexane), IR (KBr) nmax
3020, 1597, 1521 cm-1; 1H NMR (300 MHz, CDCl3): d = 8.98 (dd,
1H, J1 = 1.6 Hz, J2 = 4.3 Hz, ArH), 8.65 (s, 1H, ArH), 8.45 (dd,
1H, J1 = 1.6 Hz, J2 = 8.3 Hz, ArH), 7.74–7.63 (m, 5H, ArH), 7.37
(s, 1H, ArH), 4.22 (s, 3H, OCH3), 3.92 (s, 3H, OCH3); 13C NMR
(50 MHz, CDCl3): d = 159.2, 153.1, 150.9, 149.2, 140.5, 138.8,
138.3, 137.5, 131.9, 131.3, 130.9, 130.6, 131.4, 123.4, 122.3, 107.3,
103.5, 56.6, 56.2; mass (ES+) m/z 395.3 (M+ + 1); Anal. Calcd
for C20H15BrN2O2: C, 60.78; H, 3.83; N, 7.09; Found: C, 60.72; H,
3.87; N, 7.04.
4-(8,9-Dimethoxy-2-methylphenanthridin-6-yl)benzonitrile 6i.
Yield = 0.20 g (55%), light brown, mp >250 ◦C, Rf = 0.38 (1:5 v/v
ethylacetate/hexane), IR (KBr) nmax 3003, 2912, 2226, 1519 cm-1;
1H NMR (300 MHz, CDCl3): d = 8.25 (s, 1H, ArH), 8.07 (d, 1H,
J = 8.3 Hz, ArH), 7.97 (s, 1H, ArH), 7.90–7.83. (m, 4H, ArH),
7.56 (dd, 1H, J1 = 1.3 Hz, J2 = 8.3 Hz, ArH), 7.26 (s, 1H, ArH),
4.18 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 2.66 (s, 3H, CH3); 13C
NMR (50 MHz, CDCl3): d = 156.5, 152.7, 149.7, 145.0, 141.8,
137.2, 132.4, 130.5, 130.2, 129.3, 123.6, 121.2, 119.9, 118.8, 112.5,
107.3, 102.4, 56.3, 56.0, 22.1; mass (ES+) m/z 355.3 (M+ + 1);
Anal. Calcd for C23H18N2O2: C, 77.95; H, 5.12; N, 7.90; Found:
C, 77.87; H, 5.08; N, 7.92.
4-(8,9-Dimethoxy-6a,10a-dihydrobenzo[c][1,5] naphthyridin-6-
yl)-N,N-dimethylaniline 7c. Yield = 0.18 g (59%), yellowish
green solid, mp 157–159 ◦C, Rf = 0.26 (1:1 v/v ethylac-
1
etate/hexane), IR (KBr) nmax 2930, 1610, 1516 cm-1; H NMR
(200 MHz, CDCl3): d = 8.92 (dd, 1H, J1 = 1.6 Hz, J2 = 4.3 Hz,
ArH), 8.62 (s, 1H, ArH), 8.44 (dd, 1H, J1 = 1.7 Hz, J2 = 8.3 Hz,
ArH), 7.75–7.57. (m, 4H, ArH), 6.90 (d, 2H, J = 8.9 Hz, ArH),
6-(3,4-Dichlorophenyl)-8,9-dimethoxy-2-methyl phenanthridine
6j. Yield = 0.23 g (58%), white solid, mp 214–215 ◦C, Rf =
0.45 (1:5 v/v ethylacetate/hexane), IR (KBr) nmax 2943, 1618,
4.21 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 3.07 (s, 6H, 2 x CH3); 13
C
NMR (50 MHz, CDCl3): d = 160.7, 152.6, 151.1, 150.6, 149.5,
148.3, 145.0, 140.0, 137.2, 130.8, 130.5, 127.7, 122.8, 120.7, 112.2,
111.2, 108.3, 103.4, 56.5, 56.2, 56.1, 56.0, 40.5; mass (ES+) m/z
360.4 (M+ + 1); Molecular Formula: C22H21N3O2; MS (HR EI)
m/z calcd for [M]+ 359.1634 found 359.1624.
1
1520 cm-1; H NMR (300 MHz, CDCl3): d = 8.23 (s, 1H, ArH),
8.07 (d, 1H, J = 8.3 Hz, ArH), 7.95. (s, 1H, ArH), 7.88 (s, 1H,
ArH), 7.64–7.52 (m, 3H, ArH), 7.32 (s, 1H, ArH), 4.17 (s, 3H,
OCH3), 3.89 (s, 3H, OCH3), 2.65 (s, 3H, CH3); 13C NMR (50 MHz,
CDCl3): d = 156.0, 152.7, 149.6, 141.7, 140.2, 137.0, 133.0, 131.8,
130.5, 130.2, 130.0, 129.2, 129.0, 123.5, 121.1, 120.0, 107.5, 102.3,
56.3, 56.1, 22.2; mass (ES+) m/z 398.2 (M+ + 1); Anal. Calcd for
C22H17Cl2NO2: C, 66.34; H, 4.30; N, 3.52; Found: C, 66.39; H,
4.27; N, 3.49.
6-(4-Chlorophenyl)-8,9-dimethoxybenzo[c]phenanthridine
8a.
Yield = 0.18 g (62%), white solid, mp 215–217 ◦C, Rf = 0.43
(1:15 v/v ethylacetate/hexane), IR (KBr) nmax 3003, 2924, 1616,
1
1580 cm-1; H NMR (300 MHz, CDCl3): d = 9.40 (d, 1H, J =
8.0 Hz, ArH), 8.42 (d, 1H, J = 9.0 Hz, ArH), 7.99–7.94. (m, 3H,
ArH), 7.86 (d, 2H, J = 8.4 Hz, ArH), 7.73–7.63 (m, 2H, ArH),
7.57 (d, 2H, J = 8.4 Hz, ArH), 7.53 (s, 1H, ArH), 4.18 (s, 3H,
OCH3), 3.92 (s, 3H, OCH3); 13C NMR (50 MHz, CDCl3): d =
156.1, 152.5, 149.5, 140.3, 139.2, 134.8, 133.0, 132.3, 131.6, 130.0,
128.7, 127.6, 127.3, 127.2, 126.9, 124.9, 120.5, 120.1, 119.7, 107.2,
102.1, 56.2, 56.0 mass (ES+) m/z 400.3 (M+ + 1); Anal. Calcd for
C25H18ClNO2: C, 75.09; H, 4.54; N, 3.50; Found: C, 75.05; H,
4.59; N, 3.53.
6-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-2-methyl phenanthri-
dine 6k. Yield = 0.26 g (60%), yellow solid, mp 211–212 ◦C,
Rf = 0.15 (1:4 v/v ethylacetate/hexane), IR (KBr) nmax 2936, 2835,
1
1612, 1517 cm-1; H NMR (300 MHz, CDCl3): d = 8.22 (s, 1H,
ArH), 8.09 (d, 1H, J = 8.4 Hz, ArH), 7.95 (s, 1H, ArH), 7.52
(d, 2H, J = 4.2 Hz, ArH), 7.32–7.27 (m, 1H, ArH), 7.05 (d, 2H,
J = 8.7 Hz, ArH), 4.17 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 3.95
(s, 3H, OCH3), 3.88 (s, 3H, OCH3), 2.64 (s, 3H, CH3); 13C NMR
(50 MHz, CDCl3): d = 158.4, 152.3, 149.5, 149.3, 149.1, 142.0,
136.3, 132.6, 130.1, 129.9, 129.1, 122.4, 121.1, 113.0, 111.2, 108.5,
102.2, 56.3 56.2, 56.1, 56.0, 22.0; Molecular Formula: C24H23NO4;
mass: (ES+) m/z 390.3 (M+ + 1); MS (HR EI) m/z calcd for [M]+
389.1627 found 389.1634.
8,9-Dimethoxy-6-(4-ethoxyphenyl)benzo[c]phenanthridine 8b.
Yield = 0.16 g (59%), white solid, mp 162–165 ◦C, Rf = 0.46
(1:12 v/v ethylacetate/hexane), IR (KBr) nmax 3019, 2977, 1610,
1516 cm-1; 1H NMR (200 MHz, CDCl3): d = 9.46 (dd, 1H, J1 =
1.7 Hz, J2 = 9.4 Hz, ArH), 8.42 (d, 1H, J = 9.1 Hz, ArH),
7.98–7.85. (m, 5H, ArH), 7.74–7.60 (m, 3H, ArH), 7.12 (d, 2H,
J = 8.7 Hz, ArH), 4.16 (s, 3H, OCH3), 4.16 (q, 2H, J = 6.9 Hz,
OCH2), 3.93 (s, 3H, OCH3), 1.50 (t, 3H, J = 7.0 Hz, CH3); 13C
NMR (50 MHz, CDCl3): d = 159.5, 157.5, 153.0, 152.4, 149.3,
133.0, 132.4, 131.6, 130.0, 127.6, 127.1, 126.9, 126.7, 125.1, 119.9,
119.8, 114.5, 109.7, 107.9, 102.1, 63.7, 56.1, 56.0, 15.0; mass (ES+)
m/z 410.3 (M+ + 1); Anal. Calcd for C27H23NO3: C, 79.20; H,
5.66; N, 3.42; Found: C, 79.22; H, 5.64; N, 3.43.
6-(4-Fluorophenyl)-8,9-dimethoxy-6a,10a-dihydrobenzo [c][1,5]-
naphthyridine7a. Yield = 0.19 g (61%), white solid, mp 163–
165 ◦C, Rf = 0.48 (2:3 v/v ethylacetate/hexane), IR (KBr) nmax
3021, 1610, 1515 cm-1; 1H NMR (300 MHz, CDCl3): d = 8.97 (dd,
1H, J1 = 1.6 Hz, J2 = 4.3 Hz, ArH), 8.66 (s, 1H, ArH), 8.46 (dd,
1H, J1 = 1.6 Hz, J2 = 8.3 Hz, ArH), 7.79–7.74 (m, 2H, ArH), 7.67–
7.63 (m, 1H, ArH), 7.38 (s, 1H, ArH), 7.31–7.25 (m, 2H, ArH),
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8,9-Dimethoxy-6-(4-N,N-dimethylaminephenyl)benzo[c] phe-
nanthridine 8c. Yield = 0.16 g (60%), light yellow solid, mp
165–166 ◦C, Rf = 0.44 (1:15 v/v ethylacetate/hexane), IR (KBr)
2H, ArH), 7.09 (d, 1H, J = 8.2 Hz, ArH), 4.15 (s, 3H, OCH3), 4.02
(s, 3H, OCH3), 3.95 (s, 3H, OCH3), 3.94 (s, 3H, OCH3); 13C NMR
(50 MHz, CDCl3): d = 156.2, 152.7, 149.7, 148.9, 148.8, 139.9,
139.5, 139.3, 134.8, 133.8, 132.6, 132.2, 131.6, 130.0, 128.7, 127.2,
126.8, 126.2, 125.3, 122.6, 120.9, 120.5, 119.7, 113.8, 111.3, 107.4,
102.3, 56.4, 56.3, 56.2, 56.1; Molecular Formula: C33H26ClNO4;
mass (ES+) m/z 536.4 (M+ + 1); MS (HR EI) m/z calcd for [M]+
536.15433 found 536.15438.
n
max 3021, 1608, 1521 cm-1; 1H NMR (200 MHz, CDCl3): d = 9.48
(dd, 1H, J1 = 1.7 Hz, J2 = 9.0 Hz, ArH), 8.43 (d, 1H, J = 9.1 Hz,
ArH), 7.99–7.87 (m, 5H, ArH), 7.80 (s, 1H, ArH), 7.74–7.59 (m,
2H, ArH), 6.94 (d, 2H, J = 8.8 Hz, ArH), 4.18 (s, 3H, OCH3),
3.96 (s, 3H, OCH3), 3.09 (s, 6H, 2 x CH3); 13C NMR (50 MHz,
CDCl3): d = 157.8, 152.3, 150.9, 149.3, 140.6, 133.1, 132.5, 131.4,
130.1, 128.8, 127.5, 127.0, 126.6, 126.5, 125.2, 121.0, 119.9, 119.7,
112.2, 108.3, 102.2, 56.2, 56.1, 40.6; mass (ES+) m/z 409.3 (M+ +
1); Anal. Calcd for C27H24N2O2: C, 79.39; H, 5.92; N, 6.86; Found:
C, 79.41; H, 5.87; N, 6.88.
Acknowledgements
A.K.M., M.S. and P.K.A. are thankful to CSIR, New Delhi, for
providing a fellowship.
4-(8,9-Dimethoxybenzo[c]phenanthridin-6-yl)phenol 8d. Yield =
0.15 g (57%), white solid, mp >250 ◦C, Rf = 0.39 (1:10 v/v
ethylacetate/hexane), IR (KBr) nmax 3435, 3020, 1609, 1518 cm-1;
1H NMR (200 MHz, DMSO-d6): d = 9.82 (s, 1H, OH), 9.24 (dd,
1H, J1 = 2.7 Hz, J2 = 6.1 Hz, ArH), 8.79 (d, 1H, J = 9.2 Hz, ArH),
8.26 (s, 1H, ArH), 8.06 (d, 2H, J = 9.1 Hz, ArH), 7.78–7.62 (m,
5H, ArH), 7.0 (d, 2H, J = 8.5 Hz, ArH), 4.11 (s, 3H, OCH3), 3.83
(s, 3H, OCH3); 13C NMR (50 MHz, DMSO-d6): d = 158.0, 157.0,
152.5, 149.3, 139.3, 132.6, 131.5, 131.3, 130.9, 129.5, 127.7, 127.0,
126.6, 126.5, 124.1, 120.9, 120.0, 119.6, 115.2, 107.3, 103.0, 56.1,
55.3; mass (ES+) m/z 382.3 (M+ + 1); Anal. Calcd for C25H19NO3:
C, 78.72; H, 5.02; N, 3.67; Found: C, 78.69; H, 5.07; N, 3.71.
References
1 (a) B. D. Krane, M. O. Fagbule, M. Shamma and B. Go¨zler, J. Nat.
Prod., 1984, 47, 1–43; (b) T. Nakanishi, M. Suzuki, A. Saimoto and
T. Kabasawa, J. Nat. Prod., 1999, 62, 864–867; (c) M. Suffness,G. A.
Cordell, The Alkaloids, Academic, New York, 1985, vol. 25, pp. 178–
189; (d) Y. Barret and Y. Sauvaire, Phytotherapy Research, 1992, 6,
59–63.
2 (a) Z. Taira, M. Matsumoto, S. Ishida, T. Icikawa and Y. Sakiya, Chem.
Pharm. Bull, 1994, 42, 1556–1561; (b) Y. L. Janin, A. Croisy, J. F. Riou
and E. Bisagni, J. Med. Chem, 1993, 36, 3686–3692; (c) D. M. N.
Gakunju, E. K. Mberu, S. F. Dossaji, A. I. Gray, R. D. Waigh, P. G.
Waterman and W. M. Watkins, Antimicrob. Agents Chemother., 1995,
39, 2606–2609; (d) L. K. Wang, R. K. Johnson and S. M. Hecht, Chem.
Res. Toxicol., 1993, 6, 813–818; (e) M. Arisawa, J. M. Pezzuto, C. Bevelle
and G. A. Cordell, J. Nat. Prod., 1984, 47, 453–458; (f) J. M. Pezzuto,
S. K. Antosiak, W. M. Messmer, M. B. Slaytor and G. R. Honig, Chem.
Biol. Interact., 1983, 43, 323–339; (g) M. E. Wall, M. C. Wani and H.
Taylor, J. Nat. Prod., 1987, 50, 1095–1099; (h) D. B. Makhey, C. Yu,
A. Liu, L. F. Liu and E. J. LaVoie, Pro. Am. Assoc. Cancer. Res., 1997,
38, 22.
8,9-Dimethoxy-6-(4-nitrophenyl)benzo[c]phenanthridine
8e.
Yield = 0.19 g (65%), yellow solid, mp >250 ◦C, Rf = 0.42
(1:10 v/v ethylacetate/hexane), IR (KBr) nmax 2925, 1601, 1514,
1
1349 cm-1; H NMR (200 MHz, CDCl3): d = 9.38 (d, 1H, J =
8.7 Hz, ArH), 8.47 (d, 2H, J = 8.8 Hz, ArH), 8.12–7.96 (m, 3H,
ArH), 7.77–7.67 (m, 2H, ArH), 7.45 (s, 1H, ArH), 7.08–7.05 (m,
2H, ArH), 6.93 (d, 1H, J = 8.1 Hz, ArH), 3.95 (s, 3H, OCH3),
3.92 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3+TFA): d =
159.3, 152.8, 151.7, 150.0, 136.4, 135.0, 133.8, 132.1, 131.6, 130.5,
130.4, 129.7, 126.6, 124.5, 123.6, 123.2, 121.5, 119.8, 112.9, 112.1,
110.9, 107.5, 103.0, 57.3, 56.5; mass (ES+) m/z 411.2 (M+ + 1);
Anal. Calcd for C25H18N2O4: C, 73.16; H, 4.42; N, 6.83; Found:
C, 73.12; H, 4.45; N, 6.79.
3 A. Vogt, A. Tamewitz, J. Skoko, R. P. Sikorski, K. A. Giuliano and J. S.
Lazo, J. Biol. Chem., 2005, 280, 19078–19086.
4 (a) E. Vanquelef, M. Amoros, J. Boustie, M. A. Lynch, R. D. Waigh
and O. Duval, J. Enzyme. Inhib. Med. Chem., 2004, 6, 481–487; (b) J. M.
Nyangulu, S. L. Hargreaves, S. L. Sharples, S. P. Mackay, R. D. Waigh,
O. Duval, E. K. Mberu and W. M. Watkins, Bioorg. Med. Chem. Lett.,
2005, 15, 2007–2010.
5 (a) M. Lyse´n, J. L. Kristensen, P. Vedsø and M. Begtrup, Org. Lett.,
2002, 4, 257–259; (b) R. Alonso, P. J. Campos, B. Garc´ıa and M. A.
Rodr´ıguez, Org. Lett., 2006, 8, 3521–3523; (c) A. J. Liepa, R. N. Nearn
and D. M. J. Wright, Aust. J. Chem., 2004, 57, 473–482; (d) G. Hilt, W.
Hess and F. Schmidt, Eur. J. Org. Chem., 2005, 12, 2526–2533; (e) D.
Li, B. Zhao and E. J. LaVoie, J. Org. Chem., 2000, 65, 2802–2805;
(f) B. K. Ghorai, S. Duan, D. Jiang and J. W. Herndon, Synthesis,
2006, 21, 3661–3669; (g) D. C. Reuter, L. A. Flippin, J. McIntosh,
J. M. Caroon and J. Hammaker, Tetrahedron Lett., 1994, 35, 4899–
4902; (h) M. A. Siddiqui and V. Snieckus, Tetrahedron Lett., 1988,
29, 5463–5466; (i) B. K. Mehta, K. Yanagisawa, M. Shiro and H.
Kotsuki, Org Lett., 2003, 5, 1605–1608; (j) J. Pawlas and M. Begtrup,
Org. Lett., 2002, 4, 2687–2690; (k) T. Nakanishi and M. Suzuki, Org.
Lett., 1999, 1, 985–988; (l) P. K. Patra, J. R. Suresh, H. Ila and H.
Junjappa, Tetrahedron, 1998, 54, 10167–10178; (m) F. Gug, S. Bach,
M. Blondel, J.-M. Vierfond, A. S. Martin and H. Galons, Tetrahedron,
2004, 60, 4705–4708; (n) M. G. Banwell, D. W. Lupton, X. H. Ma, J.
Renner and M. O. Sydnes, Org. Lett., 2004, 6, 2741–2744.
6 (a) P. Mamalis and V. Petrow, J. Chem. Soc., 1950, 703–711; (b) N. P.
Buu-Ho¨ı, P. Jaquignon and C. T. Long, J. Chem. Soc., 1957, 505–509;
(c) G. J. Atwell, B. C. Baguley and W. A. Denny, J. Med. Chem., 1988,
31, 774–779.
12-(3,4-Dimethoxyphenyl)-8,9-dimethoxy benzo[c]phenanthri-
dine 8f. Yield = 0.13 g (61%), white solid, mp 225–227 ◦C, Rf =
0.41 (1:5 v/v ethylacetate/hexane), IR (KBr) nmax 3021, 2978,
1617, 1514 cm-1; 1H NMR (200 MHz, CDCl3): d = 9.51–9.47 (m,
1H, ArH), 9.34 (s, 1H, ArH), 8.32 (s, 1H, ArH), 7.99–7.91 (m,
2H, ArH), 7.81–7.73 (m, 1H, ArH), 7.66–7.58 (m, 1H, ArH), 7.44
(s, 1H, ArH), 7.22–7.10 (s, 3H, ArH), 4.14 (s, 3H, OCH3), 4.11 (s,
3H, OCH3), 4.01 (s, 3H, OCH3) 3.94 (s, 3H, OCH3); 13C NMR
(50 MHz, CDCl3): d = 153.2, 150.1, 149.9, 148.9, 148.8, 140.5,
139.4, 133.7, 132.5, 132.0, 128.8, 127.2, 126.9, 126.3, 124.9, 122.9,
122.5, 120.6, 120.2, 113.8, 111.3, 107.4, 101.8, 56.4, 56.2, 56.1;
mass (ES+) m/z 426.3 (M+ + 1); Anal. Calcd for C27H23NO4: C,
76.22; H, 5.45; N, 3.29; Found: C, 76.26; H, 5.48; N, 3.24.
6-(4-Chlorophenyl)-12-(3,4-dimethoxyphenyl)-8,9-dimethoxy
benzo[c]phenanthridine 8g. Yield = 0.17 g (66%), white solid, mp
250 ◦C, Rf = 0.39 (1:4 v/v ethylacetate/hexane), IR (KBr) nmax
7 L. R. Donaldson, D. Haigh and A. N. Hulme, Tetrahedron, 2008, 64,
4468–4477.
8 Y. Luo, Y. Mei, J. Zhang, W. Lua and J. Tanga, Tetrahedron, 2006, 62,
9131–9134.
9 M. E. Bude´n and R. A. Rossi, Tetrahedron Lett., 2007, 48, 8739–8742.
10 D. Li, B. Zhao and E. J. LaVoie, J. Org. Chem., 2000, 65, 2802–2805.
11 D. Shabashov and O. Daugulis, J. Org. Chem, 2007, 72, 7720–7725.
1
3021, 1601, 1518 cm-1; H NMR (300 MHz, CDCl3): d = 9.54–
9.51 (m, 1H, ArH), 8.34 (s, 1H, ArH), 7.99–7.88 (m, 4H, ArH),
7.75–7.70 (m, 1H, ArH), 7.64–7.57 (m, 4H, ArH), 7.22–7.16 (m,
2802 | Org. Biomol. Chem., 2009, 7, 2796–2803
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12 W.-G. Shou, Y.-Y. Yang and Y.-G. Wang, J. Org. Chem., 2006, 71,
9241–9243.
15 (a) L. Liu, Y. Zhang and Y. Wang, J. Org. Chem., 2005, 70, 6122–6125;
(b) H. Fang, G. Kaur, J. Yan and B. Wang, Tetrahedron Lett., 2005, 46,
1671–1674.
13 (a) B. Kundu, D. Sawant and R. Chhabra, J. Comb. Chem, 2005, 7,
317–321; (b) B. Kundu, D. Sawant, P. Partani and A. P. Kesarwani,
J. Org. Chem., 2005, 70, 4889–4892; (c) S. Duggineni, D. Sawant, B.
Saha and B. Kundu, Tetrahedron, 2006, 62, 3228–3241; (d) S. Sharma,
B. Saha, D. Sawant and B. Kundu, J. Comb. Chem., 2007, 9, 783–792;
(e) B. Saha, S. Sharma, D. Sawant and B. Kundu, Tetrahedron, 2008,
64, 8676–8684; (f) P. K. Agarwal, D. Sawant, S. Sharma and B. Kundu,
Eur. J. Org. Chem., 2009, 2, 292–303; (g) P. K. Agarwal, S. K. Sharma,
D. Sawant and B. Kundu, Tetrahedron, 2009, 65, 1153–1161; (h) S. K.
Sharma, S. Sharma, P. K. Agarwal and B. Kundu, Eur. J. Org. Chem.,
2009, 9, 1309–1312.
16 G. Andre´, H. Yongxin and P. Petpiboon, Tetrahedron Lett., 1997, 38,
3841–3844.
17 (a) B. Das, K. Venkateswarlu, M. Krishnaiah and H. Holla, Tetrahedron
Lett., 2006, 47, 8693–8697; (b) Z. Yanhua, S. Kazutaka and Y. Hisashi,
Synlett, 2005, 2837–2842.
18 (a) A. M. Rosa, S. Prabhakar and A. M. Lobo, Tetrahedron Lett., 1990,
31, 1881–1884; (b) M. A. Siddiqui and V. Snieckus, Tetrahedron Lett.,
1988, 29, 5463–5466.
19 J. R. Young, S. X. Huang, I. Chen, T. F. Walsh, R. J. DeVita, M. J.
Wyvratt, Jr., M. T. Goulet, N. Ren, J. Lo, Y. T. Yang, J. B. udkovitz, K.
Cheng and R. G. Smith, Bioorg. Med. Chem. Lett., 2000, 10, 1723–1727.
14 R. Leardini, A. Tundo and G. Zanardi, Synthesis, 1985, 107–109.
This journal is
The Royal Society of Chemistry 2009
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