Synthesis of polyfused heterocycle derivatives containing the dipyridoimidazole core by Friedlaender's reaction: Access to analogs of ellipticine

Article abstract of DOI:10.3987/COM-05-10354

Reaction of 3-amino-2-formylimidazo[1,2-a]pyridine with various aldehydes and ketones by Friedlaender's methodology afforded an entry to dipyridoimidazole, tri(tetra)azacyclopenta[b]fluorene, tri(tetra)azabenzo[b]- fluorene and triazaindeno[2,1-b]phenanth

Full text of DOI:10.3987/COM-05-10354

HETEROCYCLES, Vol. 65, No. 5, 2005
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HETEROCYCLES, Vol. 65, No. 5, 2005, pp. 1121 - 1137
Received, 27th January, 2005, Accepted, 11th March, 2005, Published online, 11th March, 2005
SYNTHESIS OF POLYFUSED HETEROCYCLE DERIVATIVES
CONTAINING
THE
DIPYRIDOIMIDAZOLE
CORE
BY
FRIEDLÄNDER’S REACTION: ACCESS TO ANALOGS OF
ELLIPTICINE
Nicolas Desbois,a Jean-Michel Chezal,a Florence Fauvelle,b Jean-Claude
Debouzy,b Claire Lartigue,a Alain Gueiffier,c Yves Blache,d Emmanuel
Moreau,e Jean-Claude Madelmont,a Olivier Chavignon,a and Jean-Claude
Teulade*a
a
Univ Auvergne, Clermont Ferrand, F-63001 France; Inserm, U484, Clermont
b
Ferrand, F-63000 France; CRSSA, Unit of Biophysics, La Tronche, F-38702
c
France; Univ François Rabelais, Therapeutic Chemistry Laboratory, Tours, F-
37200 France; d Univ Bourgogne, Organic Chemistry Laboratory, Dijon, F-21079
France; e CHUQ, Research Center, Québec, Canada; E-mail: j-claude.teulade@u-
clermont1.fr
Abstract – Reaction of 3-amino-2-formylimidazo[1,2-a]pyridine with various
aldehydes and ketones by Friedländer’s methodology afforded an entry to
dipyridoimidazole,
tri(tetra)azacyclopenta[b]fluorene,
tri(tetra)azabenzo[b]-
fluorene and triazaindeno[2,1-b]phenanthrene derivatives. Intercalation with a
synthetic oligodeoxynucleotide was examined.
INTRODUCTION
The ability to target specific DNA sequences using small molecules has major implications for the
clinical treatment of cancer. DNA-targeting intercalating agents have been proposed in order to avoid
some of the drawbacks common to all therapeutically useful anticancer agents. Most of the well-known
intercalating agents from natural or synthetic origin, such as anthracyclines, amsacrine or ellipticine, have
polycyclic planar moieties. Several derivatives of the alkaloid ellipticine1 (1) have been investigated for
their antitumor activity2 in which there are several examples of incorporation of an additional nitrogen

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HETEROCYCLES, Vol. 65, No. 5, 2005
atom into the tetracyclic skeleton, as with 9-aza-ellipticine or pazellipticine3 (2) (Figure 1). Recently,
cryptolepine (3) and analogs, other isosteres of ellipticine, have demonstrated cytotoxic activities toward
B16
melanoma
cells4
and
M109
Madison
lung
carcinomas.5
On
the
other
hand, tricyclic dipyridoimidazoles (with deazapurin moities) such as Glu-P-1 and Glu-P-2 (4a, b),
azaisosteres of carbolines6 have shown genotoxic and mutagenic properties.7
Figure 1
NH(CH2)3NEt2
Me
N
N
N
N
N
H
Me
2 Pazellipticine
H
Me
1 Ellipticine
R1
N
Me
N
N
N
R3
R2
N
4a Glu-P-1 R1 = NH2, R2 = H, R3 = Me
4b Glu-P-2 R1 = NH2, R2 = R3 = H
3 Cryptolepine
This is a part of our program to investigate the chemistry of some polycyclic ring systems. In particular,
imidazo[1,2-a]azines properly bifonctionalized are important synthons for the building of fused tri-, tetra-
or pentaheterocycles.8 Based on previous studies we have completed the construction of various
dipyridoimidazoles. Here we describe the synthesis of new structural analogs of Glu-P-1, P-2 and
ellipticine, using the same Friedländer's reaction as key step (Scheme 1). This work is completed by an
approach on the aromatization and insertion of a basic side chain to access ellipticine analogs.
Scheme 1
N
N
N
R1
R2
CHO
CHO
N
N
N
N
NH2
NO2
5
7
6
RESULTS AND DISCUSSION
We first synthesized the 2-formyl-3-nitroimidazo[1,2-a]pyridine (7) moiety in a few steps and with great
productivity. In preview studies, compound (7) was obtained in four steps by Moreau9 from commercial
2-aminopyridine, with an overall yield of 11%. To obtain multigram quantities of ortho-aminoaldehyde
(6), we considered an alternative method by selective nitration of 2-formylimidazo[1,2-a]pyridine10
following by reduction of nitro function. Preliminary assays of nitration failed. We therefore turned our

HETEROCYCLES, Vol. 65, No. 5, 2005
1123
attention to the direct oxidative conversion of 2-methyl-3-nitroimidazo[1,2-a]pyridine (8)11 by SeO2,
according to Odashima's procedure12 (Scheme 2). Table 1 shows the results of the oxidation of 8 with
SeO2 in dioxane.
Scheme 2
N
N
N
SeO2, dioxane
CHO
8
+
Me
+
N
N
N
∆
NO2
NO2
NO2
9
7
8
Table 1. Oxidation of compound 8 by SeO2
Equiv.
Temperature
(°C)
Reaction
time (h)
17
Product
ratioa (%)
8 (98)
Entry
of SeO2
1
2
3
4
5
2
4
90
7 (2)
7 (60)
7 (90)
7 (70)
7 (54)
Reflux
Reflux
Reflux
Reflux
57
8 (40)
6
18
8 (5)
9 (5)
9 (30)
9 (46)
7.5
10
24
72
aEstimated by 1H NMR spectroscopy.
The reaction was improved with increasing amounts of SeO2 (Entries 1-3). When a large excess of SeO2
was used, formation of demethylated 3-nitroimidazo[1,2-a]pyridine (9)11 was observed (Entries 3-5).
Optimized reaction conditions were achieved by using 6 equivalents of SeO2 (Entry 3). The purification
of compound (7) is the difficulty in this synthetic strategy. When the crude product (7) was
chromatographed using silica gel and CH2Cl2/EtOH (95/5, v/v) as eluent, the unstable hemiketal (10) was
formed in 73% yield. This compound was reduced using Sn powder in 1N HBr to afford the desired
aminoaldehyde (6) in 53% yield (Scheme 3). The overall yield of the synthesis of 6 was 12% based on 2-
aminopyridine. Because this low overall yield was unsatisfactory, another more efficient synthesis of 7
was envisaged (Scheme 4).
Scheme 3a
OH
N
N
ii
i
6
Me
N
N
OEt
NO2
NO2
8
10
aReagents and conditions: (i) (a) SeO2 (6 equiv.), dioxane, ∆; (b) SiO2, CH2Cl2,
EtOH 95:5. (ii) Sn, 1N HBr, 0 °C.
Compound (7) was prepared by nitration of 2-hydroxymethylimidazo[1,2-a]pyridine13 (11), obtained in
two steps from 2-aminopyridine with 77% overall yield, using common's methodology to afford 12,

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HETEROCYCLES, Vol. 65, No. 5, 2005
followed by oxidation with active manganese dioxide in chloroform. The preparation of 6 from 7 was
based on the same methodology previously described with compound (10). The overall yield of 6 was
26% based on 11.
Scheme 4a
N
N
N
ii
iii
i
CHO
6
CH2OH
CH2OH
N
N
N
NO2
NO2
7
12
11
aReagents and conditions: (i) H2SO4, HNO3, 0 °C. (ii) MnO2, CHCl3, ∆. (iii) 1N HBr, Sn, 0 °C.
We next applied Friedländer's methodology to 6 with various aldehydes and ketones in order to access a
wider range of potential intercalating compounds displaying tricyclic (5a-d), tetracyclic with
hydrogenated terminal ring (5e-k) or pentacyclic (5l) structures (Scheme 5).
Scheme 5a
N
R1
R2
N
X
Y
N
N
N
N
5a R1 = Me, R2 = H
5b R1 = H, R2 = Me
5c R1 = CO2Et, R2 = Me
5d R1 = H, R2 = C6H5
5e X = Y = CH2
5f X = CH2, Y = NCO2Et
5g X = NCO2Et, Y = CH2
i or ii
i
N
CHO
NH2
N
i
6
i or ii
N
X
Y
N
N
N
N
N
5h X = Y= CH2
5i X = CO, Y = CH2
5l
5j X = CH2, Y = NH, HCl
5k X = CH2, Y = CHCO2Et
aReagents and conditions: (i) appropriate carbonyl compounds, KOH (10%), EtOH, ∆. (ii)
appropriate carbonyl compounds, pyrrolidine, H2SO4, EtOH, ∆.
Under base-catalyzed conditions (KOH 10%, EtOH), compounds (5a-e, 5h-j and 5l) were obtained in 53-
85% yields. For the carbamates (5f, g and ester 5k), the reaction must be carried out under mild
conditions14 in the presence of pyrrolidine and catalytic sulfuric acid. We have noted that the solution
must be purged with argon for 10 min, otherwise low yields and by-products can be observed.15 We next

HETEROCYCLES, Vol. 65, No. 5, 2005
1125
focused our attention on the aromatization of tetracyclic compounds (5h, j and k). Access to ellipticine
analog (13b) was obtained by MnO2 oxidation17 of tetrahydro structure (5j) (Scheme 6). Similarly,
aromatization of compounds (5h, k) with 10% Pd/C in dichlorobenzene or diglyme18 was unsuccessful,
only led to starting materials. Oxidation of 5h was achieved using DDQ19 in toluene to afford tetracycle
(13a) in 16% yield. When this reaction was extended to 5k, a longer reaction time was needed, and the
unstable compound (13c) was isolated in low yield (6%).
Scheme 6a
N
N
i
X
X
N
N
N
N
or ii
13a X = CH
13b X = N
13c X = C-CO2Et
5h X = CH2
5j X = NH, HCl
5k X = CH-CO2Et
aReagents and conditions: (i) From 5h, k: DDQ, toluene, ∆. (ii) From 5j: (a) 40% NaOH;
(b) MnO2, AcOEt, ∆.
It has been demonstrated in many cases that the insertion of a basic side chain into a DNA intercalator can
induce an increase both in binding affinity and in solubility under physiological conditions.20 A basic side
chain could easily be installed on the carboxylate function of 5k by condensation of N,N-
dimethylethylenediamine in the presence of trimethylaluminum to give 14 in 74% yield (Scheme 7).
Scheme 7a
O
N
NMe2
N
H
i
5k
5i
N
N
N
N
14
NMe2
+
OH
HN
N
N
N
ii
N
15
16
β
γ
OH
Me2N
N
Me2N
N
O
α
N
iii
5i
N
N
N
18
17
aReagents and conditions: (i) NH2(CH2)2NMe2, AlMe3, CH2Cl2, ∆. (ii) (a)
NH2(CH2)2NMe2, p-toluenesulfonic acid, benzene, ∆; (b) NaBH4, EtOH. (iii)
Me2N(CH2)3MgCl, THF, ∆.
Alternatively the basic side chain could be introduced on 5i by two ways: the first consists of the
condensation of N,N-dimethylethylenediamine followed by reduction with NaBH4 to afford the desired

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HETEROCYCLES, Vol. 65, No. 5, 2005
compound 15 (77%) and reduced compound 16 (13%), and the second uses the Grignard reaction using
(3-(dimethylamino)propyl)magnesium chloride to give 17 and an unexpected structure 18 in 22% and 4%
yields, respectively (Similar reactions have been observed at low temperature or with steric hindered
ketone).21 In a preliminary screening we evaluated the intercalation properties of five different tri (5d),
tetra (13b, 14 and 15) or pentacycle (5l) structures. Their interactions with synthetic oligodeoxynucleotide
d(CGATCG)2 were studied by NMR spectroscopy.22 For example no or weak variations of chemical shift
(δ) of DNA or 14 (Figure 2) were observed in spectra of the DNA/14 mixture. Therefore, it can be
concluded that this compound did not interact significantly with oligodeoxynucleotide. As for compound
(14) the other molecules (5d, 5l, 13b and 15) exhibited only an unspecific interaction with DNA.
Figure 2: schematic diagram of the half (CGATCG)2 molecule, where sites of interaction with 14 are
represented by grey circles: small: δ∆ >0.04 ppm, middle-sized δ∆ > 0.06 ppm and large δ∆ >0.1 ppm.
5'-C1 p G2 p A3 p T4 p C5 p G6 -3'
3'-G6 p C5 p T4 p A3 p G2 p C1-5'
3'
CH3
N
O
O
P
5'
O
O
O
T4
2'
A3
N
CH2
N
3'
4'
O
1'
O
O
5'
H2C
O
O
P
N
O
N
O
O
P
O
C5
O
G2
N
O
CH2
O
O
N
O
O
O
O
H2C
P
O
O
O
N
O
O
O
P
CH2
O
G6
C1
O
N
N
O
N
OH
3'
H2C
OH 5'
CONCLUSION
Several new polyheterocycles such as dipyridoimidazole and polyazafluorene derivatives have been
synthesized by Friedländer’s approach in imidazo[1,2-a]pyridine serie with 53-93% yields (excepted for
5g). Aromatization of tetracyclic compounds (5h, j-k) gave the new analogs of ellipticine (13a-c).
EXPERIMENTAL
Instrumentation. All column chromatography was performed with Merck neutral aluminum oxide 90
standardized (63-200 µm) or silica gel A normal phase (35-70 µm). All thinlayer chromatography was

HETEROCYCLES, Vol. 65, No. 5, 2005
1127
performed on Merck neutral aluminum oxide 60F254 plates or Merck silica gel 60F254 plates. The plates
were visualized with UV light (254 nm). Melting points were determined on an electrothermal IA9300
1
13
(capillary) and are not corrected. NMR (500, 400 or 200 MHz for H or 100 or 50 MHz for C) were
recorded on a Bruker Avance 500, a Bruker Avance 400 or Bruker AM 200 instruments using CDCl3,
DMSO-d6 or D2O as solvent. Infrared spectra were recorded on a FTIR Nicolet impact 410. MS spectral
analyses were performed on a Hewlett-Packard 5985B or 5989A instrument. All air-sensitive reactions were
run under argon atmosphere. All solvents were dried using common techniques.
2-Ethoxyhydroxymethyl-3-nitroimidazo[1,2-a]pyridine (10). To a solution of dioxane (100 mL) and
water (0.61 mL) were added 2-methyl-3-nitroimidazo[1,2-a]pyridine11 (8) (1.00 g, 5.65 mmol) and
selenium dioxide (3.73 g, 33.6 mmol). The solution was stirred at reflux for 18 h. After cooling to rt, the
solution was diluted with H2O (50 mL), basified with saturated aqueous solution of Na2CO3 (5 mL) and
extracted with CH2Cl2 (3x100 mL). The organic layers were dried with Na2SO4 and concentrated in
vacuo. The crude product (7) was chromatographed to obtain hemiketal (10) (SiO2, CH2Cl2/EtOH,
95/5, v/v); (0.98 g, 73%); Rf: 0.20 (SiO2, CH2Cl2/EtOH, 95/5, v/v); mp 90-92 °C (from H2O/ethanol 3/5);
IR (KBr) 3400-3000, 1474, 1370, 1312, 1206 cm-1; MS m/z 237 (M+, 9), 221 (6), 206 (9), 163 (10), 105
1
(29), 94 (19), 79 (35), 78 (100), 51 (49); H NMR (DMSO-d6, 200 MHz) δ 1.12 (t, 3H, J = 7 Hz, CH3),
3.32-3.84 (m, 2H, CH2), 6.16 (d, 1H, J = 9.5 Hz, OH), 6.89 (d, 1H, J = 9.5 Hz, CH-OH), 7.45 (t, 1H, J =
13
7 Hz, H-6), 7.80 (m, 1H, H-7), 7.92 (d, 1H, J = 8.5 Hz, H-8), 9.33 (d, 1H, J = 7 Hz, H-5); C NMR
(DMSO-d6, 50 MHz) δ 15.6 (CH3), 62.9 (CH2), 91.1 (C-acetal), 117.8 (C-8 or C-6), 118.4 (C-6 or C-8),
128.6 (C-5), 132.3 (C-7), 144.7 (C-2), 150.8 (C-8a), (C-3) not observed. Anal. Calcd for C10H11N3O4: C,
50.63; H, 4.67; N, 17.71. Found: C, 50.53; H, 4.68; N, 17.70.
2-Hydroxymethyl-3-nitroimidazo[1,2-a]pyridine (12). To a solution of concentrated H2SO4 (4 mL)
cold to –5 °C were added 2-hydroxymethylimidazo[1,2-a]pyridine13 (11) (0.40 g, 2.07 mmol) and HNO3
(d 1.40, 0.45 mL). The mixture was stirred at rt for 4 h. The solution was poured on ice (50 g), neutralized
with saturated aqueous Na2CO3 solution (4 mL) and extracted with CH2Cl2 (3x50 mL). The combined
organic layers were dried and concentrated in vacuo and the residue was chromatographed (Al2O3,
CH2Cl2/EtOH, 98/2, v/v) to give compound (12); (0.32 g, 61%); Rf: 0.55 (Al2O3, CH2Cl2/EtOH, 98/2,
v/v); mp 170-172 °C (from ether); IR (KBr) 3300-2900, 1397, 1382, 1216 cm-1; MS m/z 193 (M+, 19),
1
176 (26), 118 (28), 105 (28), 78 (100), 51 (32); H NMR (DMSO-d6, 200 MHz) δ 4.92 (s, 2H, CH2), 7.45
(t, 1H, J = 7 Hz, H-6), 7.81 (m, 1H, H-7), 7.93 (d, 1H, J = 9 Hz, H-8), 9.37 (d, 1H, J = 7 Hz, H-5); 13C
NMR (DMSO-d6, 50 MHz) δ 58.7 (CH2), 117.1 (C-6 or C-8), 117.6 (C-8 or C-6), 128.0 (C-5), 128.3

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HETEROCYCLES, Vol. 65, No. 5, 2005
(C-3), 131.9 (C-7), 144.9 (C-2), 153.7 (C-8a). Anal. Calcd for C8H7N3O3: C, 49.74; H, 3.65; N, 21.75.
Found: C, 49.62; H, 3.64; N, 21.71.
2-Formyl-3-nitroimidazo[1,2-a]pyridine (7). To a solution of chloroform (40 mL) and 2-
hydroxymethyl-3-nitroimidazo[1,2-a]pyridine (12) (1.50 g, 7.77 mmol) was added manganese dioxide23
(3.40 g, 39.1 mmol). The solution was stirred at reflux for 4 h. After cooling to rt, the solution was
filtered on celite, the precipitate was washed with chloroform (50 mL) and the organic layer was
concentrated in vacuo. The recrystallization from H2O/ethanol (3/5) provided pure product (7) (1.36 g,
92%); mp 110-112 °C; (lit.,9 113-115 °C); 1H NMR (CDCl3, 400 MHz) δ 7.48 (t, 1H, J = 7 Hz, H-6), 7.79
13
(m, 1H, H-7), 8.03 (d, 1H, J = 9 Hz, H-8), 9.49 (d, 1H, J = 7 Hz, H-5), 10.84 (s, 1H, CHO); C NMR
(CDCl3, 100 MHz) δ 118.8 (C-6 or C-8), 120.4 (C-8 or C-6), 127.5 (C-5), 131.8 (C-7), 136.2 (C-3), 141.7
(C-2), 144.5 (C-8a), 184.9 (CHO).
General procedure for reduction of nitro compounds (7) and (10). The appropriate nitro compound
(4.30 mmol) and small fractions of tin powder (1.02 g, 8.60 mmol) were added to a cold (0 °C) stirred
solution containing 1N HBr (25 mL). The mixture was stirred at 0 °C for 2 h, and allowed to rt. Water (20
mL) was added and the solution was neutralized with saturated aqueous Na2CO3 (20 mL). The aqueous
layer was concentrated under reduced pressure and the residue was chromatographed (Al2O3,
CH2Cl2/EtOH, 98/2, v/v) to give 3-amino-2-formylimidazo[1,2-a]pyridine (6) from 7: yield 46% or
from 10: yield 53%; Rf: 0.40 (Al2O3, CH2Cl2/EtOH, 98/2, v/v); mp > 400 °C (from H2O/ethanol 6/1); IR
(KBr) 3390, 3296, 3216, 1661, 1638, 1622, 1565, 1260 cm-1; MS m/z 161 (M+, 84), 144 (85), 105 (67),
79 (71), 78 (100), 51 (65);1H NMR (DMSO-d6, 400 MHz) δ 6.79 (t, 1H, J = 7 Hz, H-6), 7.08 (m, 3H,
NH2, H-7), 7.33 (d, 1H, J = 9 Hz, H-8), 8.23 (d, 1H, J = 7 Hz, H-5), 9.90 (s, 1H, CHO); 13C NMR
(DMSO-d6, 100 MHz) δ 111.8 (C-6), 118.6 (C-8), 122.5 (C-3), 123.6 (C-5), 124.6 (C-7), 138.6 (C-8a),
138.8 (C-2), 185.0 (CHO). Anal. Calcd for C8H7N3O: C, 59.62; H, 4.38; N, 26.07. Found: C, 59.51; H,
4.38; N, 26.11.
General procedure for Friedländer’s reaction. To a stirred solution of dry EtOH (10 mL) (previously
degassed with dry argon) was added 3-amino-2-formylimidazo[1,2-a]pyridine (6) (0.20 g, 1.24 mmol), a
solution of KOH (0.13 g, 2.32 mmol) in EtOH (1.4 mL) or pyrrolidine (113 µL, 1.36 mmol) and
concentrated H2SO4 (3.3 µL) followed by appropriate aldehyde or ketone (2.23 mmol). The solution was
refluxed for 4 h. After cooling to rt, the solution was concentrated under vacuo. The residue was purified
by column chromatography to afford 5a-k respectively.

HETEROCYCLES, Vol. 65, No. 5, 2005
1129
3-Methyldipyrido[1,2-a;3’,2’-d]imidazole (5a). From propanal; (Al2O3, CH2Cl2); (74%); Rf: 0.45
(Al2O3, CH2Cl2); mp 118-120 °C (from hexane); IR (KBr) 1549, 1252 cm-1; MS m/z 183 (M+, 100), 182
(48), 155 (12), 78 (44), 51 (32); 1H NMR (CDCl3, 200 MHz) δ 2.57 (s, 3H, CH3), 6.92 (t, 1H, J = 7 Hz,
H-8), 7.51 (m, 1H, H-7), 7.66 (d, 1H, J = 9 Hz, H-6), 8.00 (s, 1H, H-4), 8.31 (s, 1H, H-2), 8.76 (d, 1H,
13
J = 7 Hz, H-9); C NMR (CDCl3, 50 MHz) δ 19.2 (CH3), 111.0 (C-8), 117.9 (C-6), 124.6 (C-9), 127.1
(C-4), 131.2 (C-7), 131.8 (C-3), 136.5 (C-4a), 140.1 (C-10a), 143.4 (C-2) ,148.6 (C-5a). Anal. Calcd for
C11H9N3: C, 72.11; H, 4.95; N, 22.94. Found: C, 71.99; H, 4.95; N, 23.01.
2-Methyldipyrido[1,2-a;3’,2’-d]imidazole (5b). From acetone; (SiO2, AcOEt); (67%); Rf: 0.10 (Al2O3,
CH2Cl2); mp 130-132 °C (from hexane); (lit.,24 149-151 °C).
Ethyl 2-methyldipyrido[1,2-a;3’,2’-d]imidazole-3-carboxylate (5c). From ethyl acetoacetate; (Al2O3,
CH2Cl2/EtOH, 99/1, v/v); (85%); Rf: 0.65 (Al2O3, CH2Cl2/EtOH, 99/1, v/v); mp 143-145 °C (from
ether/ethanol 10/1); IR (KBr) 1718, 1640, 1401, 1248 cm-1; MS m/z 255 (M+, 100), 226 (46), 210 (27),
182 (55), 181 (84), 170 (22), 78 (76), 51 (34); 1H NMR (CDCl3, 400 MHz) δ 1.43 (t, 3H, J = 7 Hz, CH3),
2.98 (s, 3H, CH3), 4.42 (q, 2H, J = 7 Hz, CH2), 6.89 (t, 1H, J = 7 Hz, H-8), 7.48 (m, 1H, H-7), 7.63 (d,
1H, J = 9 Hz, H-6), 8.73 (m, 2H, H-9, H-4); 13C NMR (CDCl3, 100 MHz) δ 14.3 (CH3), 25.2 (CH3), 61.4
(CH2), 111.2 (C-8), 118.3 (C-6), 124.1 (C-3), 124.7 (C-9), 130.4 (C-4), 131.3 (C-7), 134.3 (C-4a), 142.5
(C-10a), 149.4 (C-5a), 153.3 (C-2), 167.0 (CO). Anal. Calcd for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46.
Found: C, 66.10; H, 5.11; N, 16.41.
2-Phenyldipyrido[1,2-a;3’,2’-d]imidazole (5d). From acetophenone; (Al2O3, CH2Cl2); (68%); Rf: 0.52
(Al2O3, CH2Cl2); mp 94-96 °C (from H2O/ethanol 1/1); IR (KBr) 1638, 1491, 1400 cm-1; MS m/z 245
(M+, 100), 140 (9), 78 (27), 51 (21); 1H NMR (CDCl3, 400 MHz) δ 6.92 (t, 1H, J = 6.5 Hz, H-8), 7.43 (t,
1H, J = 7 Hz, H-Ph), 7.50 (m, 3H, H-7, 2H-Ph), 7.67 (d, 1H, J = 9 Hz, H-6), 7.97 (d, 1H, J = 8.5 Hz,
13
H-3), 8.15 (d, 2H, J = 7 Hz, 2H-Ph), 8.24 (d, 1H, J = 8.5 Hz, H-4), 8.88 (d, 1H, J = 6.5 Hz, H-9); C
NMR (CDCl3, 100 MHz) δ 110.9 (C-8), 118.2 (C-6), 119.2 (C-3), 124.8 (C-9), 127.1 (2C-Ph), 127.9
(C-4), 128.7 (C-Ph), 128.9 (2C-Ph), 131.1 (C-7), 135.9 (C-4a), 139.4 (C-Ph), 141.9 (C-10a), 149.1
(C-5a), 150.5 (C-2). Anal. Calcd for C16H11N3: C, 78.35; H, 4.52; N, 17.13. Found: C, 78.40; H, 4.52; N,
17.10.
2,3-Dihydro-1H-4,4b,9-triazacyclopenta[b]fluorene (5e). From cyclopentanone; (SiO2, AcOEt); (72%);
Rf: 0.13 (SiO2, AcOEt); mp 166-168 °C (from H2O/ethanol 2/1); IR (KBr) 1498, 1389 cm-1; MS m/z 209
1
(M+, 100), 208 (77), 78 (33), 51 (27); H NMR (CDCl3, 200 MHz) δ 2.12 (quint., 2H, J = 7.5 Hz, H-2),

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3.00 (m, 4H, H-1, H-3), 6.70 (t, 1H, J = 7 Hz, H-6), 7.28 (m, 1H, H-7), 7.49 (d, 1H, J = 9 Hz, H-8), 7.83
13
(s, 1H, H-10), 8.59 (d, 1H, J = 7 Hz, H-5); C NMR (CDCl3, 100 MHz) δ 24.3 (C-2), 30.8 (C-1), 33.9
(C-3), 110.5 (C-6), 117.9 (C-8), 122.9 (C-10), 124.1 (C-5), 129.8 (C-7), 135.8 (C-4a), 136.1 (C-10a),
140.7 (C-9a), 147.8 (C-8a), 159.4 (C-3a). Anal. Calcd for C13H11N3: C, 74.62; H, 5.30; N, 20.08. Found:
C, 74.90; H, 5.31; N, 20.14.
Preparation of compounds (5g) and (5f). From ethyl 3-oxotetrahydro-1H-pyrrole-1-carboxylate25 (6.16
mmol) with pyrrolidine (1.36 mmol) and H2SO4 (0.06 mmol); (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give in
order of elution: ethyl 2,3-dihydro-1,4,4b,9-tetraazacyclopenta[b]fluorene-1-carboxylate (5g) (25%);
Rf: 0.46 (Al2O3, CH2Cl2/EtOH, 99/1, v/v); mp 172-174 °C (from ether/ethanol 10/1); IR (KBr) 1693,
1
1309 cm-1; MS m/z 282 (M+, 100), 254 (26), 210 (30), 209 (76), 182 (26), 78 (26), 51 (9); H NMR
(CDCl3, 400 MHz) δ 1.37 (m, 6H, CH3, CH3’), 3.40 (t, 4H, J = 8.5 Hz, H-3, H-3’), 4.19 (t, 4H,
J = 8.5 Hz, H-2, H-2’), 4.34 (m, 4H, CH2, CH2’), 6.82 (t, 2H, J = 7 Hz, H-6, H-6’), 7.36 (m, 2H, H-7, H-
7’), 7.55 (d, 2H, J = 9 Hz, H-8, H-8’), 8.10 (br s, 1H, H-10), 8.49 (br s, 1H, H-10’), 8.61 (d, 2H, J = 7 Hz,
13
H-5, H-5’); C NMR (CDCl3, 100 MHz) δ 14.7 (CH3, CH3’), 29.2 (C-3, C-3’), 46.6 (C-2, C-2’), 61.7
(CH2, CH2’), 110.9 (C-6), 111.8 (C-6’), 117.8 (C-8, C-8’), 123.8 (C-5, C-5’), 129.6 (C-7, C-7’), 136.1,
136.3, 136.7, 137.0 (C-10a, C-10a’, C-4a, C-4a’), 148.2 (C-9a, C-9a’, C-8a, C-8a’), 153.2 (C-3a), 153.8
(C-3a’), 166.9 (CO, CO’). Anal. Calcd for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.59; H,
5.01; N, 19.91. Ethyl 1,3-dihydro-2,4,4b,9-tetraazacyclopenta[b]fluorene-2-carboxylate (5f) (53%);
Rf: 0.42 (Al2O3, CH2Cl2/EtOH, 99/1, v/v); mp 229-231 °C (from ether/ethanol 10/1); IR (KBr) 1706,
1112 cm-1; MS m/z 282 (M+, 34), 253 (100), 209 (95), 182 (15), 78 (33), 51 (12); 1H NMR (CDCl3, 400
MHz) δ 1.35 (t, 6H, J = 7 Hz, CH3, CH3’), 4.26 (q, 4H, J = 7 Hz, CH2, CH2’), 4.88 (m, 8H, H-1, H-1’,
H-3, H-3’), 6.91 (t, 2H, J = 7 Hz, H-6, H-6’), 7.49 (m, 2H, H-7, H-7’), 7.64 (d, 2H, J = 9 Hz, H-8, H-8’),
13
8.02 (m, 2H, H-10, H-10’), 8.74 (m, 2H, H-5, H-5’); C NMR (CDCl3, 100 MHz) δ 14.8 (CH3, CH3’),
50.6, 50.8, 52.0, 52.3 (C-1, C-1’, C-3, C-3’), 61.5 (CH2, CH2’), 111.0 (C-6, C-6’), 118.1 (C-8), 118.2
(C-8’), 121.6 (C-10), 121.8 (C-10’), 124.4 (C-5), 124.5 (C-5’), 129.0 (C-10a), 129.3 (C-10a’), 130.9
(C-7), 131.0 (C-7’), 136.4 (C-4a, C-4a’), 141.8 (C-9a, C-9a’), 148.8 (C-8a, C-8a’), 150.6 (C-3a), 150.9
(C-3a’), 155.1 (CO), 155.2 (CO’). Anal. Calcd for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C,
63.72; H, 4.99; N, 19.80. The products (5f) and (5g) existed as a mixture of two rotamers.
6,7,8,9-Tetrahydro-4a,5,11-triazabenzo[b]fluorene (5h). From cyclohexanone; (Al2O3, CH2Cl2);
(81%); Rf: 0.44 (Al2O3, CH2Cl2); mp 102-104 °C (from H2O/ethanol 3/1); IR (KBr) 1494, 1400 cm-1;
MS m/z 223 (M+, 100), 195 (55), 78 (34), 51 (20); 1H NMR (CDCl3, 400 MHz) δ 1.88 (m, 2H, H-8), 1.95
(m, 2H, H-7), 3.00 (t, 2H, J = 6 Hz, H-9), 3.11 (t, 2H, J = 6 Hz, H-6), 6.82 (t, 1H, J = 7 Hz, H-3), 7.41

HETEROCYCLES, Vol. 65, No. 5, 2005
1131
13
(m, 1H, H-2), 7.60 (d, 1H, J = 9 Hz, H-1), 7.84 (s, 1H, H-10), 8.71 (d, 1H, J = 7 Hz, H-4); C NMR
(CDCl3, 50 MHz) δ 22.9 (C-8 or C-7), 23.2 (C-7 or C-8), 29.7 (C-9), 32.9 (C-6), 110.2 (C-3), 117.8
(C-1), 124.4 (C-4), 127.0 (C-10), 130.3 (C-2), 131.0 (C-9a), 135.2 (C-4b), 139.9 (C-10a), 147.7 (C-11a),
151.2 (C-5a). Anal. Calcd for C14H13N3: C, 75.31; H, 5.87; N, 18.82. Found: C, 75.52; H, 5.85; N, 18.80.
7,8-Dihydro-6H-4a,5,11-triazabenzo[b]fluoren-9-one (5i). From 1,3-cyclohexanedione; (Al2O3,
CH2Cl2); (72%); Rf: 0.23 (Al2O3, CH2Cl2); mp 202-204 °C (from H2O/ethanol 4/1); IR (KBr) 1678,
1639, 1471, 1392 cm-1; MS m/z 237 (M+, 100), 209 (17), 208 (16), 181 (72), 78 (32), 51 (17); 1H NMR
(CDCl3, 200 MHz) δ 2.26 (m, 2H, H-7), 2.75 (t, 2H, J = 6 Hz, H-8), 3.29 (t, 2H, J = 6 Hz, H-6), 6.87 (t,
1H, J = 7 Hz, H-3), 7.49 (m, 1H, H-2), 7.63 (d, 1H, J = 9 Hz, H-1), 8.68 (d, 1H, J = 7 Hz, H-4), 8.77 (s,
13
1H, H-10); C NMR (CDCl3, 50 MHz) δ 22.7 (C-7), 33.3 (C-6), 39.1 (C-8), 111.2 (C-3), 118.2 (C-1),
124.5 (C-4), 126.7 (C-9a), 126.8 (C-10), 131.5 (C-2), 135.2 (C-10a), 143.4 (C-4b), 149.4 (C-11a), 156.7
(C-5a), 197.1 (CO). Anal. Calcd for C14H11N3O: C, 70.87; H, 4.67; N, 17.71. Found: C, 71.10; H, 4.66;
N, 17.73.
6,7,8,9-Tetrahydro-4a,5,8,11-tetraazabenzo[b]fluorene hydrochloride (5j). From 4-piperidinone;
(Al2O3, CH2Cl2/EtOH, 98/2, v/v) followed by treatment with 11% HCl-ether (2 mL), the solution was
concentrated under vacuo started again with dry ether (15 mL) and filtered; (0.16 g, 57%); Rf: 0.16
(Al2O3, CH2Cl2/EtOH, 95/5, v/v); mp 318-320 °C (from ether/ethanol 10/1); MS m/z (base) 224 (M+,
58), 223 (34), 195 (100), 78 (39), 51 (20); IR (KBr) 3600-3300, 2924, 2766, 1640, 1520 cm-1; 1H NMR
(D2O, 200 MHz) δ 3.49 (t, 2H, J = 6.5 Hz, H-7 or H-6), 3.75 (t, 2H, J = 6.5 Hz, H-6 or H-7), 4.71 (s, 2H,
H-9), 7.64 (t, 1H, J = 7 Hz, H-3), 8.00 (d, 1H, J = 9 Hz, H-1), 8.26 (m, 2H, H-2, H-10), 9.15 (d, 1H,
J = 7 Hz, H-4); 13C NMR (D2O, 50 MHz) δ 27.9 (C-7 or C-6), 41.7 (C-6 or C-7), 44.4 (C-9), 112.4 (C-1),
117.2 (C-3), 122.3 (C-10), 123.8 (C-9a), 126.0 (C-10a), 126.4 (C-4), 138.3 (C-4b), 140.4 (C-2), 143.4
(C-11a or C-5a), 148.6 (C-5a or C-11a). Anal. Calcd for C13H13N4Cl: C, 59.89; H, 5.03; N, 21.49. Found:
C, 60.11; H, 5.03; N, 21.54.
Ethyl 6,7,8,9-tetrahydro-4a,5,11-triazabenzo[b]fluorene-8-carboxylate (5k). From ethyl 4-
oxocyclohexanecarboxylate with pyrrolidine (1.36 mmol) and H2SO4 (0.06 mmol); (SiO2, CH2Cl2/EtOH,
95/5, v/v); (93%); Rf: 0.09 (SiO2, CH2Cl2/EtOH, 95/5, v/v); mp 124-126 °C (from H2O/ethanol 3/1); IR
(KBr) 3000-2800, 2974, 1732 cm-1; MS m/z 295 (M+, 82), 222 (33), 221 (100), 220 (71), 207 (18), 78
1
(36), 51 (10); H NMR (CDCl3, 400 MHz) δ 1.22 (t, 3H, J = 7 Hz, CH3), 2.10-2.30 (m, 2H, H-7), 2.78
(m, 1H, H-8), 3.10-3.18 (m, 4H, H-9, H-6), 4.13 (q, 2H, J = 7 Hz, CH2), 6.78 (t, 1H, J = 7 Hz, H-3), 7.37
13
(m, 1H, H-2), 7.54 (d, 1H, J = 9 Hz, H-1), 7.84 (s, 1H, H-10), 8.66 (d, 1H, J = 7 Hz, H-4); C NMR

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HETEROCYCLES, Vol. 65, No. 5, 2005
(CDCl3, 100 MHz) δ 14.3 (CH3), 26.0 (C-7), 31.8 (C-9 or C-6), 31.9 (C-6 or C-9), 39.7 (C-8), 60.7 (CH2),
110.5 (C-3), 118.0 (C-1), 124.5 (C-4), 127.2 (C-10), 128.9 (C-9a), 130.6 (C-2), 135.5 (C-4b), 140.4
(C-10a), 148.6 (C-11a), 149.7 (C-5a), 174.9 (CO). Anal. Calcd for C17H17N3O2: C, 69.14; H, 5.80; N,
14.23. Found: C, 69.40; H, 5.80; N, 14.22.
5,6-Dihydro-8,12a,13-triazaindeno[2,1-b]phenanthrene (5l). From α-tetralone; (Al2O3, CH2Cl2/EtOH,
99/1, v/v); (53%); Rf: 0.80 (Al2O3, CH2Cl2/EtOH, 99/1, v/v); mp 144-146 °C (from H2O/ethanol 2/1); IR
1
(KBr) 1493, 1395 cm-1; MS m/z 271 (M+, 100), 270 (72), 78 (24), 51 (13); H NMR (CDCl3, 500 MHz) δ
3.05 (t, 2H, J = 7 Hz, C-5), 3.21 (t, 2H, J = 7 Hz, H-6), 6.93 (t, 1H, J = 7 Hz, H-11), 7.31 (d, 1H,
J = 7 Hz, H-4), 7.36 (t, 1H, J = 7.5 Hz, H-3), 7.45 (t, 1H, J = 7 Hz, H-2), 7.50 (m, 1H, H-10), 7.69 (d, 1H,
13
J = 9 Hz, H-9), 8.02 (s, 1H, H-7), 8.52 (d, 1H, J = 8 Hz, H-1), 8.90 (d, 1H, J = 7 Hz, H-12); C NMR
(CDCl3, 100 MHz) δ 28.5 (C-5), 29.3 (C-6), 110.6 (C-11), 118.0 (C-9), 124.7 (C-12), 125.1 (C-1), 125.9
(C-7), 127.1 (C-2), 127.8 (C-4), 128.7 (C-3), 130.6 (C-10), 131.3 (C-6a), 135.0 (C-13b), 136.2 (C-7a),
138.3 (C-4a), 141.0 (C-12b), 146.2 (C-13a), 148.8 (8a). Anal. Calcd for C18H13N3: C, 79.68; H, 4.83; N,
15.49. Found: C, 79.80; H, 4.83; N, 15.48.
4a,5,11-Triazabenzo[b]fluorene (13a). To a solution of 5h (0.20 g, 0.90 mmol) in dry toluene (20 mL)
was added a solution of DDQ (0.41 g, 1.78 mmol) in dry toluene (5 mL). The solution was stirred at
reflux for 48 h. Then a solution of DDQ (0.41 g, 1.78 mmol) in dry toluene (5 mL) was added and the
solution was stirred at reflux for 93 h. After cooling to rt, the solution was filtered and concentrated under
vacuo. The crude product was chromatographed (Al2O3, AcOEt) to give 13a (40 mg, 16%); Rf: 0.77
(Al2O3, AcOEt); mp 152-154 °C (from H2O/ethanol 6/1); IR (KBr) 1644, 1516 cm-1; MS m/z 219 (M+,
100), 114 (11), 78 (32), 51 (15); 1H NMR (CDCl3, 400 MHz) δ 6.92 (t, 1H, J = 7 Hz, H-3), 7.60 (m, 2H,
H-7, H-2), 7.68 (d, 1H, J = 9 Hz, H-1), 7.75 (t, 1H, J = 7 Hz, H-8), 8.10 (d, 1H, J = 8 Hz, H-9), 8.25 (d,
1H, J = 9 Hz, H-6), 8.64 (s, 1H, H-10), 8.94 (d, 1H, J = 7 Hz, H-4); 13C NMR (CDCl3, 100 MHz) δ 110.4
(C-3), 118.2 (C-1), 124.6 (C-10), 125.1 (C-8), 125.8 (C-4), 128.1 (C-7), 128.3 (C-9a), 128.4 (C-6) ,128.5
(C-9), 133.7 (C-2), 136.0 (C-10a), 144.0 (C-4b), 144.3 (C-5a), 151.9 (C-11a). Anal. Calcd for C14H9N3:
76.70; H, 4.14; N, 19.17. Found: C, 76.45; H, 4.13; N, 19.15.
4a,5,8,11-Tetraazabenzo[b]fluorene (13b). The hydrochloride (5j) (0.13 g, 0.50 mmol) was diluted with
H2O (5 mL), and treated with 40% NaOH (0.5 mL, 7.75 mmol). The aqueous solution was extracted with
CH2Cl2 (3x10 mL). The organic layers were dried (Na2SO4) and concentrated under vacuo. The crude
6,7,8,9-tetrahydro-4a,5,8,11-tetraazabenzo[b]fluorene obtained (0.10 g, 0.45 mmol) was refluxed with
23
AcOEt (5 mL) and MnO2 (1.17 g, 13.4 mmol) during 3 h. After cooling to rt, the solution was filtered

HETEROCYCLES, Vol. 65, No. 5, 2005
1133
and concentrated under vacuo. The crude product was chromatographed (Al2O3, AcOEt) to give 13b (30
mg, 28%); Rf: 0.49 (Al2O3, AcOEt); mp 152-154 °C (from H2O/ethanol 2/1); IR (KBr) 1647, 1393 cm-1;
MS m/z 220 (M+, 100), 78 (24), 51 (11); 1H NMR (CDCl3, 400 MHz) δ 6.97 (t, 1H, J = 7 Hz, H-3), 7.65
(m, 1H, H-2), 7.70 (d, 1H, J = 9 Hz, H-1), 8.05 (d, 1H, J = 6 Hz, H-6); 8.74 (d, 1H, J = 6 Hz, H-7), 8.77
(s, 1H, H-10), 8.91 (d, 1H, J = 8 Hz, H-4), 9.55 (s, 1H, H-9); 13C NMR (CDCl3, 100 MHz) δ 111.0 (C-3),
118.4 (C-1), 121.2 (C-6), 123.7 (C-9a), 125.0 (C-10), 125.8 (C-4), 134.4 (C-2), 136.7 (C-10a), 144.3
(C-7), 145.6 (C-5a), 146.9 (C-4b), 152.7 (C-11a), 153.7 (C-9). Anal. Calcd for C13H8N4: C, 70.90; H,
3.66; N, 25.44. Found: C, 71.02; H, 3.66; N, 25.41.
Ethyl 4a,5,11-triazabenzo[b]fluorene-8-carboxylate (13c). To a solution of 5k (0.21 g, 0.71 mmol) in
dry toluene (20 mL) under argon atmosphere was added a solution of DDQ (0.34 g, 1.48 mmol) in dry
toluene (5 mL). The solution was stirred at reflux for 21 h. After cooling to rt, a solution of DDQ (0.17 g,
0.74 mmol) in dry toluene (5 mL) was added and the solution was stirred at reflux for 24 h. After cooling
to rt, the solution was filtered and concentrated under reduced pressure. The crude product was
chromatographed (Al2O3, AcOEt) to give 13c (10 mg, 6%); Rf: 0.82 (Al2O3, AcOEt); mp > 400 °C (from
H2O/ethanol 6/1); IR (KBr) 1702, 1262 cm-1; MS m/z 291 (M+, 100), 263 (70), 246 (35), 218 (50), 217
(26), 78 (32), 51 (16); 1H NMR (CDCl3, 400 MHz) δ 1.48 (t, 3H, J = 7 Hz, CH3), 4.48 (q, 2H, J = 7 Hz,
CH2), 6.94 (t, 1H, J = 7 Hz, H-3), 7.62 (m, 2H, H-2), 7.68 (d, 1H, J = 9.5 Hz, H-1), 8.26 (d, 1H, J = 9 Hz,
H-6), 8.32 (d, 1H, J = 9 Hz, H-7), 8.74 (s, 1H, H-9 or H-10), 8.88 (s, 1H, H-10 or H-9), 8.92 (d, 1H,
J = 7 Hz, H-4); Anal. Calcd for C17H13N3O2: C, 70.09; H, 4.50; N, 14.42. Found: C, 69.99; H, 4.48; N,
14.41.
N-[2-(Dimethylamino)ethyl]-6,7,8,9-tetrahydro-4a,5,11-triazabenzo[b]fluorene-8-carboxamide (14).
N,N-Dimethylethylenediamine (0.045 g, 0.51 mmol) and trimethylaluminum (2.0 M solution in hexanes)
(0.31 mL, 0.64 mmol) were added dropwise at 0 °C to a stirred solution of dry CH2Cl2 (10 mL). After
addition of compound (5k) (0.10 g, 0.34 mmol) the mixture was refluxed for 24 h and N,N-
dimethylethylenediamine (45 mg, 0.51 mmol) and trimethylaluminum (2.0 M solution in hexanes)
(0.31 mL, 0.64 mmol) were added. Then the solution was stirred at reflux for 24 h. After cooling to rt,
water (15 mL) was added and the mixture was basified with saturated aqueous Na2CO3 (20 mL) and
extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude
product was chromatographed (Al2O3, CH2Cl2/EtOH, 97/3, v/v) to give 14 (85 mg, 74%); Rf: 0.29
(Al2O3, CH2Cl2/EtOH, 97/3, v/v); mp 200-202 °C (from ether/ethanol 10/1); IR (KBr) 3424, 3291, 2933,
1
1637 cm-1; MS m/z 337 (M+, 5), 267 (6), 222 (8), 220 (8), 78 (7), 71 (15), 58 (100), 51 (2); H NMR
(CDCl3, 400 MHz) δ 2.25 (s, 6H, 2CH3), 2.48 (t, 1H, J = 6 Hz, H-9), 2.66 (m, 1H, H-8), 3.00-3.30 (m,

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HETEROCYCLES, Vol. 65, No. 5, 2005
6H, H-6, H-7,CH2-NH), 3.39 (m, 2H, CH2-N), 6.83 (t, 1H, J = 7 Hz, H-3), 7.43 (m, 1H, H-2), 7.59 (d,
13
1H, J = 9.5 Hz, H-1), 7.87 (s, 1H, H-10), 8.70 (d, 1H, J = 7 Hz, H-4); C NMR (CDCl3, 100 MHz) δ
26.8, 32.0, 32.7, 36.6 (C-6, C-7, C-9, CH2-NH), 41.5 (C-8), 45,0 (2CH3), 57.8 (CH2-N), 110.4 (C-3),
117.9 (C-1), 124.5 (C-4), 127.1 (C-10), 130.6 (C-2), 129.2 (C-9a), 135.4 (C-4b), 140.2 (C-10a), 148.4
(C-11a or C-5a), 149.7 (C-5a or C-11a), 174.9 (CO). Anal. Calcd for C19H23N5O: C, 67.63; H, 6.87; N,
20.76. Found: C, 67.42; H, 6.89; N, 20.70.
Condensation of 5i with N,N-dimethylethylenediamine. A mixture of 5i (0.30 g, 1.27 mmol) and N,N-
dimethylethylenediamine (1.67 g, 18.9 mmol) in anhydrous benzene (10 mL) was refluxed in the
presence of a catalytic amount of p-toluenesulfonic acid, and the formed H2O was azeotropically distilled
off and collected with a Dean-stark trap for 48 h. After cooling, the solvent was evaporated, and the crude
intermediate Schiff’s base was dissolved in dry ethanol (10 mL) and treated with NaBH4 (96 mg, 2.52
mmol) for 2 h at rt, under argon. Then the solvent was removed under reduced pressure, and the residue
was partitioned between H2O (20 mL) and CH2Cl2 (20 mL). The separated organic layer was dried
(Na2SO4) and concentrated in vacuo to give a crude residue which was chromatographed (Al2O3,
CH2Cl2/EtOH, 99/1, v/v) to give in order of elution: N,N-dimethyl-N’-(6,7,8,9-tetrahydro-4a,5,11-
triazabenzo[b]fluoren-9-yl)ethylene-1,2-diamine (15) (0.30 g, 77%); Rf: 0.33 (Al2O3, CH2Cl2/EtOH,
97/3, v/v); mp 108-110 °C (from ether/ethanol 10/1); IR (KBr) 3600-3200, 1500, 1399 cm-1; MS m/z 309
(M+, 31), 251 (13), 222 (55), 207 (15), 78 (16), 58 (100), 51 (3); 1H NMR (CDCl3, 400 MHz) δ 1.80-2.20
(m, 4H, H-7, H-8), 2.22 (s, 6H, 2CH3), 2.47 (t, 2H, J = 6 Hz, CH2-N), 2.80 (m, 2H, CH2-NH), 3.11 (m,
2H, H-6), 4.01 (t, 1H, J = 5 Hz, H-9), 6.83 (t, 1H, J = 7 Hz, H-3), 7.42 (m, 1H, H-2), 7.60 (d, 1H,
13
J = 9 Hz, H-1), 8.17 (s, 1H, H-10), 8.72 (d, 1H, J = 7 Hz, H-4); C NMR (CDCl3, 100 MHz) δ 19.0
(C-7), 28.3 (C-8), 32.8 (C-6), 44.3 (CH2-NH), 45.4 (2CH3), 56.3 (C-9), 59.1 (CH2-N), 110.4 (C-3), 117.9
(C-1), 124.5 (C-4), 127.3 (C-10), 130.5 (C-2), 133.3 (C-9a), 135.3 (C-10a), 140.5 (C-4b), 148.4 (C-11a),
151.5 (C-5a). Anal. Calcd for C18H23N5: C, 69.87; H, 7.49; N, 22.63. Found: C, 70.11; H, 7.52; N, 22.61.
6,7,8,9-Tetrahydro-4a,5,11-triazabenzo[b]fluoren-9-ol (16) (70 mg, 13%); Rf: 0.11 (Al2O3,
CH2Cl2/EtOH, 99/1, v/v); mp 154–156 °C; (from ether/ethanol 10/1); IR (KBr) 3500-3200, 1641, 1498,
1401 cm-1; MS m/z 239 (M+, 93), 221 (100), 220 (58), 210 (45), 183 (48), 182 (49), 78 (75), 51 (28); 1H
NMR (CDCl3, 400 MHz) δ 2.00 (m, 4H, H-7, H-8), 2.97 (m, 2H, H-6), 4.95 (t, 1H, J = 7 Hz, H-9), 6.79
(t, 1H, J = 7 Hz, H-3), 7.38 (m, 1H, H-2), 7.53 (d, 1H, J = 9.5 Hz, H-1), 8.13 (s, 1H, H-10), 8.61 (d, 1H,
13
J = 7 Hz, H-4); C NMR (CDCl3, 100 MHz) δ 18.8 (C-7), 32.0 (C-8), 32.7 (C-6), 68.4 (C-9), 110.7
(C-3), 117.8 (C-1), 124.5 (C-4), 127.4 (C-10), 130.9 (C-2), 133.7 (C-9a or C-10a), 134.9 (C-10a or C-9a),
140.6 (C-4b), 148.5 (C-11a), 151.0 (C-5a). Anal. Calcd for C14H13N3O: C, 70.28; H, 5.48; N, 17.56.
Found: C, 70.03; H, 5.47; N, 17.52.

HETEROCYCLES, Vol. 65, No. 5, 2005
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Grignard reaction of 5i with dimethylaminopropylmagnesium chloride. A Grignard reagent was
prepared from magnesium (0.19 g, 7.82 mmol) suspended in dry tetrahydrofuran (10 mL) by addition of
3-dimethylaminopropyl chloride26 (1.00 g, 8.23 mmol) in dry tetrahydrofuran (5 mL). The reaction was
initiated by addition of ethyl bromide (0.05 mL) and a crystal of iodine. The Grignard reagent was
refluxed for 2 h. Then compound (5i) (0.90 g, 3.80 mmol) was added and the stirred mixture was refluxed
for 21 h. After cooling, a solution of saturated aqueous ammonium chloride (90 mL) was added and the
mixture was extracted with CH2Cl2 (3x50 mL). The organic layer was dried (Na2SO4) and concentrated in
vacuo to afford a residue which was chromatographed (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give in order
of elution: 9-(3-dimethylaminopropyl)-6,7,8,9-tetrahydro-4a,5,11-triazabenzo[b]fluoren-9-ol (17)
(0.27 g, 22%); Rf: 0.10 (Al2O3, CH2Cl2/EtOH, 99/1, v/v); mp 144-146 °C (from H2O/ethanol 3/1); IR
1
(KBr) 3500-3300, 1640, 1396 cm-1; MS m/z 324 (M+, 1), 306 (3), 78 (8), 58 (100), 51 (2); H NMR
(CDCl3, 400 MHz) δ 1.48-1.68 (m, 2H, H-β), 1.75-2.20 (m, 6H, H-α, H-8, H-7), 2.25 (s, 6H, 2CH3), 2.32
(m, 2H, H-γ), 3.07 (m, 2H, H-6), 6.76 (t, 1H, J = 6 Hz, H-3), 7.36 (m, 1H, H-2), 7.55 (d, 1H, J = 8.5 Hz,
13
H-1), 8.40 (s, 1H, H-10), 8.63 (d, 1H, J = 7 Hz, H-4); C NMR (CDCl3, 100 MHz) δ 19.6 (C-7), 22.0
(C-β), 32.7 (C-6), 35.6 (C-8), 42.7 (C-α), 45.2 (2CH3), 60.1 (C-γ), 71.5 (C-9) 110.3 (C-3), 117.9 (C-1),
124.4 (C-4), 125.6 (C-10), 130.4 (C-2), 135.4 (C-10a), 139.4 (C-9a), 140.3 (C-4b), 148.4 (C-11a), 150.2
(C-5a). Anal. Calcd for C19H24N4O: C, 70.34; H, 7.46; N, 17.27. Found: C, 70.23; H, 7.45; N, 17.28. 10-
(3-Dimethylaminopropyl)-7,8-dihydro-6H-4a,5,11-triazabenzo[b]fluoren-9-one (18) (50 mg, 4%); Rf:
0.17 (Al2O3, CH2Cl2/EtOH, 99/1, v/v); mp 89-91 °C (from H2O/ethanol 8/1); IR (KBr) 1672, 1638, 1383
1
cm-1; MS m/z 322 (M+, 3), 264 (8), 251 (100), 78 (14), 72 (16), 58 (84), 51 (5); H NMR (CDCl3, 400
MHz) δ 1.85 (q, 2H, J = 7.5 Hz, H-β), 2.16 (m, 2H, H-7), 2.22 (s, 6H, 2CH3), 2.48 (t, 2H, J = 7.5 Hz,
H-γ), 2.71 (t, 2H, J = 7 Hz, H-8), 3.25 (t, 2H, J = 7 Hz , H-6), 3.58 (m, 2H, H-α), 6.82 (t, 1H, J = 7 Hz,
13
H-3), 7.41 (m, 1H, H-2), 7.62 (d, 1H, J = 9 Hz, H-1), 8.64 (d, 1H, J = 7 Hz, H-4); C NMR (CDCl3,
100 MHz) δ 21.9 (C-7), 27.0 (C-α), 28.0 (C-β), 34.5 (C-6), 40.9 (C-8), 45.4 (2CH3), 59.9 (C-γ), 111.2
(C-3), 118.5 (C-1), 124.6 (C-9a), 124.7 (C-4), 131.0 (C-2), 135.9 (C-10a), 141.6 (C-4b), 147.9 (C-10),
148.7 (C-11a), 158.7 (C-5a), 199.8 (CO). Anal. Calcd for C19H22N4O: C, 70.78; H, 6.88; N, 17.38. Found:
C, 70.89; H, 6.88; N, 17.38.
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