Synthesis of new heterocyclic ring systems via [1,3,5]triazino[1,2-a] benzimidazole derivatives

Article abstract of DOI:10.1002/jhet.5570420725

Three new heterocyclic ring systems were synthesized from [1,3,5]triazino[1,2-a]benzimidazole derivatives, which in turn were obtained by condensation of 2-guanidinobenzimidazole with o-substituted benzaldehydes.

Full text of DOI:10.1002/jhet.5570420725

Nov-Dec 2005
1417
Synthesis of New Heterocyclic Ring Systems
via [1,3,5]Triazino[1,2-a]benzimidazole Derivatives
§
Giampaolo Primofiore, Federico Da Settimo, Gianluca Pardi, Francesca Simorini,*
Concettina La Motta, Silvia Salerno, Sabrina Taliani and Anna Maria Marini
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy
Received March 30, 2005
§
The Authors dedicate this article to the memory of Professor Antonio Da Settimo, who
was an example of excellence in science and in life for them.
Three new heterocyclic ring systems were synthesized from [1,3,5]triazino[1,2-a]benzimidazole deriva-
tives, which in turn were obtained by condensation of 2-guanidinobenzimidazole with o-substituted ben-
zaldehydes.
J. Heterocyclic Chem., 42, 1417 (2005).
Introduction.
DNA. Moreover, the structure-activity relationships
showed that both the length and the steric hindrance of the
side chains are crucial for cytotoxicity [5].
DNA replication constitutes the necessary condition for
cell division and, consequently, it has become one of the
preferred targets for the development of new drugs that are
able to interrupt the proliferation of neoplastic cells.
Among the DNA-binding agents, the intercalators repre-
sent one of the most important classes. Generally, they are
characterized by the presence of a planar or pseudo-planar,
aromatic or heteroaromatic chromophore, to which flexi-
ble basic side chains may be bound to improve DNA-inter-
calating properties [1-2].
Pursuing our interest in nitrogen chromophores contain-
ing the benzimidazole nucleus, in this paper we describe
the easy preparation of some fused benzimidazoles repre-
senting three new heterocyclic ring systems: the isoindolo-
[2',1':5,6][1,3,5]triazino[1,2-a]benzimidazole 3, the benz-
imidazo[1',2':3,4][1,3,5]triazino[1,2-c]quinazoline 6 and
1
the benzimidazo[1,2-a][1,3,3a ,4,6]pentaazaacephen-
anthrylenes 7a,b and 9 (Figure 1).
On the basis of these considerations, in carrying out a
program to prepare new potential DNA-intercalating
agents, in recent papers we described some tetracyclic
derivatives containing the purine, benzimidazole or indole
nucleus [3-5]. The benzimidazole derivatives functional-
ized with dialkylaminoalkyl side chains have a cytotoxic
activity mainly through an intercalative mode of binding to
Results and Discussion.
The synthetic procedures utilized in the preparation of
the new compounds described in this paper were based on
the review of a paper where it was reported that [1,3,5]tri-
azino[1,2-a]benzimidazole derivatives A (Figure 2) are
readily available from a condensation of 2-guanidinobenz-
imidazole with benzaldehydes in refluxing ethanol or N,N-
dimethylformamide [6].
Figure 2
We realized that compounds A could be useful precur-
sors in the synthesis of new nitrogen-bearing chro-
mophores if an appropriate R group were introduced in the
2' position by reacting 2-guanidinobenzimidazole with an
o-substituted benzaldehyde. The R group, as such or after
conversion into a reactive moiety, could form a new ring
derivative B by reaction with 3-NH in the presence of a
coupling agent (Figure 2).
Figure 1

1418
G. Primofiore, F. Da Settimo, G. Pardi, F. Simorini, C. La Motta, S. Salerno, S. Taliani
and A. M. Marini
Vol. 42
As a first example of the potential of compounds A, we
2' position. The diamino derivative 5 was obtained by cat-
alytic hydrogenation of the nitro compound 4 [7], which,
in turn, was prepared by reacting 1 and o-nitrobenzalde-
hyde in refluxing N,N-dimethylformamide. The structure
of 4 and 5 was confirmed by analytical and spectral data.
now describe the synthetic route to the isoindolotriazino-
benzimidazole derivative 3 (Scheme 1), which represents a
new heterocyclic ring system. The new triazinobenzimida-
zole intermediate 2 was obtained through the reaction of 2-
guanidinobenzimidazole 1 with o-carboxybenzaldehyde in
refluxing ethanol. The structure of 2 was confirmed by ana-
1
The H nmr spectra of both compounds revealed the pres-
ence of the 4-H proton's singlet (7.34 ppm for 4 and 6.75
1
13
lytical and spectral data and, in particular, the H nmr spec-
ppm for 5), and their C nmr spectra showed a peak in the
trum of 2 exhibited a singlet (7.22 ppm) relative to the 4-H
proton. The C nmr spectrum showed a peak at 170.90 ppm
saturated carbon range due to the C-4 carbon (62.36 ppm
for 4 and 63.22 ppm for 5).
13
due to the carboxyl moiety and a peak at 63.60 ppm, which
was assigned to the C-4 carbon, the only sp hybridized car-
bon of the molecule. The presence of a signal due to a satu-
rated carbon let us discard the isomeric azomethine structure
2a for the carboxylic acid derivative (Figure 3).
The condensation of the diamino compound 5 with
triphosgene in tetrahydrofuran led to the formation of the
quinazoline derivative 6, which represents a new hetero-
cyclic ring system (Scheme 2). The structure of 6 agreed
3
1
with analytical and spectral data. In particular, in the H
nmr spectrum the presence was observed of a singlet at
6.82 ppm, which was assigned to the 15a-H proton, and the
13
C nmr spectrum showed a diagnostic signal at 66.90 ppm
due to the C-15a carbon, the only saturated carbon of the
molecule.
The reaction between the diamino derivative 5 and 2-
ketoacids seemed to be interesting from a synthetic point
of view because, in principle, the double functionality of
the latter could be exploited to assemble new polyhetero-
cyclic scaffolds. Therefore, we made 5 react with 2-
ketoacids and examined the outcome of those condensa-
tions as shown in Scheme 3.
Figure 3
Cyclization of 2 to the desired lactam 3 was effected by
heating the former with an excess of polyphosphoric acid
(Scheme 1). The most interesting features of the nmr spectra
of compound 3 were the signals of the atoms in the 13b posi-
tion of the nucleus: the proton absorbed at 7.00 ppm as a sin-
When compound 5 was reacted with glyoxylic acid or
pyruvic acid in refluxing ethanol for 24 and 2 hours, the
products were the pentaazaacephenanthrylene derivatives
7a or 7b, respectively, which represent a new heterocyclic
ring system. Their structure was confirmed by analytical
and spectral data, especially by their nmr spectra, which
3
glet and the sp hybridized carbon resonated at 69.68 ppm.
To further explore the reactivity of derivatives A for the
obtainment of new polyheterocyclic compounds, we syn-
thesized the new key intermediate 5 (Scheme 2), which
was characterized by the presence of an amino group in the
1
showed important similarities, as expected. The H nmr
spectrum of 7a was characterized by two singlets at 5.35
ppm and 7.07 ppm, which were assigned to the 5a-H and
14a-H proton, respectively. The proton nmr spectrum of 7b
exhibited the 14a-H proton's singlet at 7.17 ppm and
another singlet integrating for three protons at 1.67 ppm
due to the methyl group linked to the 5a position. In the
13
3
C nmr spectrum of 7a there were two peaks in the sp
hybridized carbon range at 62.62 ppm and 67.92 ppm,
which were assigned to the C-14a and C-5a carbon,
respectively. Compound 7b had three saturated carbon
atoms resonating at 23.31 ppm (CH ), 61.73 ppm (C-14a)
3
and 72.98 ppm (C-5a).
Based on the fact that the scaffolds of compounds
7a,b had two saturated carbon atoms, we supposed that
they formed through the mechanistic pathway illus-
trated in Scheme 4, according to which the imino inter-
mediates 10a,b cyclized to the quinazoline derivatives
11a,b by the addition of 3-NH to the imino double bond.
Finally, the carboxylic acids 11a,b looses water
intramolecularly to afford the hexacyclic ring systems

Nov-Dec 2005
Synthesis of New Heterocyclic Ring Systems
1419
7a,b. Incidentally, we isolated none of the aforemen-
tioned intermediates because shorter reaction times only
resulted in recovering mixtures of unreacted 5 and
either compound 7a or compound 7b.
13
14a-H proton. For what regards the C nmr spectrum of
9, apart from the ethyl signals at 8.03 ppm and 29.13
ppm, it revealed the presence of two more sp hybridized
3
carbon atoms resonating at 61.98 ppm (C-14a) and 76.55
ppm (C-5a) in accordance with the carbon nmr spectra of
7a,b. There was also a chemical confirmation of the
structure of 9 as this compound formed when the inter-
mediate 8 was refluxed in absolute ethanol for 48 hours
(Scheme 3).
On the base of the reaction mechanism outlined above,
the intermediate that we isolated and then cyclized to 9
could be the carboxylic acid 8a (Figure 4) in alternative to
the 8 reported in Scheme 3. The low solubility of the inter-
When the diamino derivative 5 and 2-ketobutyric acid
were refluxed in absolute ethanol, we obtained either the
iminobutyric acid 8 or the pentaazaacephenanthrylene
derivative 9 (Scheme 3), depending on the reaction time
(3 hours or 48 hours, respectively). The structure of
product 9, which is the same ring system as 7a,b, was
1
supported by analytical and spectral data. In its H nmr
spectrum we noted that the ethyl group showed a triplet
at 0.91 ppm and a multiplet at 1.90-2.19 ppm because the
CH protons, being linked to the chiral carbon 5a, were
13
2
mediate prevented us from taking the C nmr spectrum,
diastereotopic and coupled to each other besides the CH
3
which could help us to assign either the imino structure 8
or the quinazoline scaffold 8a to the compound because
the latter has one saturated carbon more than the former.
Therefore, lacking the carbon nmr data and based on the
protons. Also, there was a singlet at 7.10 ppm due to the
1
H nmr spectrum, we ruled out the formation of the quina-
zoline derivative 8a because the CH protons of the ethyl
2
group didn't couple to each other and showed a quartet at
2.54 ppm: if the structure were 8a, the CH protons would
2
be diastereotopic due to their proximity to a chiral center
and could exhibit a multiplet like the CH protons of com-
2
1
pound 9. Another feature of the H nmr spectrum of com-
pound 8 was the presence of a singlet at 6.66 ppm due to
the 4-H proton.
Figure 4

1420
G. Primofiore, F. Da Settimo, G. Pardi, F. Simorini, C. La Motta, S. Salerno, S. Taliani
and A. M. Marini
Vol. 42
2-Amino-4-(2-carboxyphenyl)-3,4-dihydro-1,3,5-triazino[1,2-a]-
benzimidazole (2).
o-Carboxybenzaldehyde (2.55 g, 17.0 mmol) was added to a
stirred suspension of 2-guanidinobenzimidazole 1 (2.80 g, 16
mmol) in ethanol (50 mL) and the mixture was refluxed for 4
hours. After cooling, the solid that precipitated from the resulting
solution was collected, washed with ethanol and recrystallized
from N,N-dimethylformamide to give 4.22 g (84% yield) of pure 2,
-1
white solid, mp 266-268 °C dec; ir (cm ): ν
3398, 3150,
MAX
1
1660, 1625, 1602, 1580, 1567, 1514; H nmr: δ 6.49 (d, 1H), 6.84
(d, 1H), 7.03 (dd, 1H), 7.14-7.41 (m, 4H, ArH + 4-H at 7.22), 7.89-
7.94 (m, 2H), 10.50 (s, 1H, exchangeable with deuterium oxide);
C nmr: δ 63.60 (C-4), 110.40, 112.90, 123.00, 124.00, 124.80,
129.10, 129.30, 130.70, 131.80, 132.10, 137.60, 138.00, 152.80,
13
+
157.30, 170.90 (COOH); ms (m/z, %): 307 (M , 2), 158 (100).
Anal. Calcd. for C
H N O : C, 62.53; H, 4.26; N, 22.79.
16 13 5 2
Found: C, 62.28; H, 4.26; N, 22.39.
7-Aminoisoindolo[2',1':5,6][1,3,5]triazino[1,2-a]benzimidazole-
9(13bH)-one (3).
A stirred mixture of compound 2 (1.00 g, 3.26 mmol) and
polyphosphoric acid (10.00 g) was heated at 180 °C for 2 hours.
The hot mixture was poured into ice and neutralized (pH 6-7)
with 30% ammonium hydroxide solution. The precipitate was
collected, washed with water and recrystallized from N,N-
The isolation of compound 8a was not possible because
dimethylformamide to give 0.90 g (97% yield) of pure 3, pale
refluxing 8 in absolute ethanol for 48 hours led to 9
together with a small amount of unreacted 8, while shorter
reaction times only resulted in major amounts of recovered
starting material.
-1
yellow solid, mp 210-212 °C; ir (cm ): ν
3375, 1720, 1600,
MAX
1
1520, 1280, 735; H nmr: δ 7.00-7.13 (m, 3H, ArH + 13b-H at
7.00), 7.40 (d, 1H), 7.57 (d, 1H), 7.75 (br s, 1H, exchangeable
with deuterium oxide), 7.81-7.88 (m, 1H), 8.01-8.08 (m, 2H),
8.45 (br s, 1H, exchangeable with deuterium oxide), 8.53 (d, 1H);
C nmr: δ 69.68 (C-13b), 110.99, 118.14, 121.09, 122.16,
125.73, 128.48, 131.28, 132.19, 132.34, 134.89, 138.16, 144.17,
Conclusions.
13
The easily available triazinobenzimidazole derivatives A
proved to be a useful tool for the preparation of new poly-
heterocyclic ring systems containing the benzimidazole
nucleus and their synthetic potential can be further developed
by reacting them with a number of types of coupling agents.
The fused benzimidazoles obtained can function as
intermediates in the synthesis of potential antitumor
+
150.67, 155.04, 165.40; ms (m/z, %): 289 (M , 12), 73 (100).
Anal. Calcd. for C
H N O: C, 66.43; H, 3.81; N, 24.22.
16 11 5
Found: C, 66.72; H, 3.92; N, 24.60.
2-Amino-4-(2-nitrophenyl)-3,4-dihydro-1,3,5-triazino[1,2-a]-
benzimidazole (4).
A stirred solution of 2-guanidinobenzimidazole 1 (2.80 g, 16
mmol) and o-nitrobenzaldehyde (2.44 g, 16 mmol) in N,N-
dimethylformamide (30 mL) was refluxed for 1 hour. After cool-
ing, the solid that precipitated was collected, washed with ethanol
agents, since they bear NH or NH groups to which dialky-
2
laminoalkyl side chains can be linked.
and recrystallized from ethanol to give 2.156 g (43% yield) of
EXPERIMENTAL
-1
pure 4, orange solid, mp 247-248 °C; ir (cm ): ν
3392,
MAX
1
3317, 3057, 1652, 1611, 1583, 1344, 1241, 811, 740; H nmr: δ
General.
6.52 (br s, 2H, 2-NH , exchangeable with deuterium oxide),
2
6.58-6.62 (m, 1H), 6.74-6.82 (m, 1H), 6.90-7.00 (m, 2H), 7.29 (d,
1H), 7.34 (s, 1H, 4-H), 7.60-7.65 (m, 2H), 7.84 (br s, 1H, 3-H,
exchangeable with deuterium oxide), 8.18-8.23 (m, 1H); C nmr
Melting points were determined using a Reichert Köfler hot-
stage apparatus and are uncorrected. Infrared spectra were
recorded with a NICOLET/AVATAR 360 FT-IR spectrophotome-
13
1
13
(methanol-d ): δ 62.36 (C-4), 108.34, 116.15, 120.70, 122.27,
ter as nujol mulls. H nmr spectra (200 MHz) and C nmr spec-
4
125.55, 127.22, 130.59, 130.88, 133.90, 134.71, 141.90, 147.67,
tra (50 MHz) were recorded in dimethylsulfoxide-d solution,
6
+
153.86, 156.01; ms (m/z, %): 308 (M , 100).
unless otherwise stated, on a Varian Gemini 200 spectrometer.
Mass spectra were obtained on a FINNIGAN POLARIS/GCQ
PLUS spectrometer using a direct exposure probe and an electron
beam energy of 70 eV. Evaporations were performed in vacuo
(rotary evaporator). Analytical tlc was carried out on Merck 0.2
Anal. Calcd. for C
H N O : C, 58.44; H, 3.90; N, 27.27.
15 12 6 2
Found: C, 58.04; H, 3.70; N, 26.96.
2-Amino-4-(2-aminophenyl)-3,4-dihydro-1,3,5-triazino[1,2-a]-
benzimidazole (5).
mm precoated silica gel aluminium sheets (60 F ). Elemental
254
analyses were performed by our Analytical Laboratory and
agreed with theoretical values to within 0.4%.
To a solution of compound 4 (0.90 g, 2.92 mmol) in ethanol
(300 mL) was added PtO ·xH O (0.07 g) and the mixture was
2
2

Nov-Dec 2005
Synthesis of New Heterocyclic Ring Systems
1421
stirred under hydrogen at atmospheric pressure until the theoretical
uptake of hydrogen was achieved (5 hours). The catalyst was
removed by filtration and the filtrate was concentrated to a small
lected, washed with ethanol and recrystallized from N,N-dimethyl-
formamide-water to give 0.184 g (52% yield) of pure 7b, white
-1
solid, mp 286-288 °C dec; ir (cm ): ν
3297, 1669, 1614, 1590,
MAX
1
volume to afford 0.523 g (64 % yield) of pure 5, white solid, mp
1388, 1300, 1221, 1187, 1150, 740, 631; H nmr: δ 1.67 (s, 3H,
CH ), 6.24 (d, 1H), 6.46-6.54 (m, 1H), 6.78-6.82 (m, 1H), 7.05-7.13
-1
225-226 °C; ir (cm ): ν
3304, 3221, 3147, 1651, 1607, 1577,
MAX
3
1
1522, 1504, 1395, 1238, 757, 740; H nmr: δ 5.40 (br s, 2H, 2'-
NH , exchangeable with deuterium oxide), 6.42 (br s, 2H, 2-NH ,
(m, 1H), 7.17 (s, 1H, 14a-H), 7.22-7.31 (m, 2H), 7.42 (br s, 1H,
exchangeable with deuterium oxide), 7.52-7.63 (m, 2H), 12.27 (br
2
2
13
exchangeable with deuterium oxide), 6.50 (t, 1H), 6.60 (d, 1H),
6.70-6.79 (m, 3H, ArH + 4-H at 6.75), 6.88-6.95 (m, 2H), 7.05 (t,
1H), 7.21 (d, 1H), 7.82 (br s, 1H, 3-H, exchangeable with deu-
s, 1H, exchangeable with deuterium oxide); C nmr: δ 23.31
(CH ), 61.73 (C-14a), 72.98 (C-5a), 109.61, 115.48, 118.34 (2C),
3
120.59, 122.78 (2C), 123.83, 130.41, 133.07, 141.60, 141.81,
13
+
terium oxide); C nmr: δ 63.22 (C-4), 108.89, 116.57, 116.89,
149.78, 160.00, 176.00; ms (m/z, %): 330 (M , 12), 145 (100).
117.24, 119.50, 121.36, 122.49, 127.99, 130.43, 132.14, 144.05,
Anal. Calcd. for C
H N O: C, 65.45; H, 4.24; N, 25.45.
18 14 6
+
146.65, 154.68, 156.43; ms (m/z, %): 278 (M , 48), 261 (100).
Found: C, 65.27; H, 4.43; N, 25.85.
Anal. Calcd. for C
Found: C, 64.97; H, 5.27; N, 30.59.
H N : C, 64.75; H, 5.04; N, 30.22.
15 14 6
2-[2-(2-Amino-3,4-dihydro-1,3,5-triazino[1,2-a]benzimidazol-
4-yl)phenylimino]butyric acid (8).
8-Aminobenzimidazo[1',2':3,4][1,3,5]triazino[1,2-c]quinazoline-
6(5H,15aH)-one (6).
A stirred suspension of compound 5 (0.20 g, 0.72 mmol) and
2-ketobutyric acid (0.074 g, 0.72 mmol) in absolute ethanol (30
mL) was refluxed for 3 hours. After cooling, the solid was col-
A stirred suspension of compound 5 (0.20 g, 0.72 mmol) in
anhydrous tetrahydrofuran (40 mL) was cooled to about –25 °C
and triphosgene (0.086 g, 0.29 mmol) was added, followed by the
dropwise addition of a solution of triethylamine (0.24 mL, 1.74
mmol) in anhydrous tetrahydrofuran (10 mL). The mixture was
then stirred at –20 to –10 °C for 5 hours. The solid was collected,
washed with water and recrystallized from ethanol to give 0.056
lected and washed with ethanol to give 0.191 g (70% yield) of
-1
pure 8, white solid, mp 263-266 °C dec.; ir (cm ): ν
3372,
MAX
3188, 1689, 1624, 1600, 1518, 1290, 1238, 1081, 1047, 887, 866,
846, 818, 740; H nmr: δ 1.31 (t, 3H, CH ), 2.49-2.59 (q, 2H,
CH ), 6.62-6.72 (m, 3H, Ar-H + 4-H at 6.66), 6.95-7.36 (m, 9H),
10.64 (br s, 1H, exchangeable with deuterium oxide); C nmr:
too insoluble to take the spectrum; ms (m/z, %): 344 (M -H O,
1
3
2
13
-1
+
g (26% yield) of pure 6, white solid, mp 237-238 °C; ir (cm ):
2
ν
3345, 3276, 1699, 1641, 1604, 1539, 1334, 1310, 1255,
39), 159 (100).
Anal. Calcd. for C
22.11. Found: C, 59.97; H, 5.23; N, 21.50.
MAX
1
1078, 770, 730, 712; H nmr: δ 5.97 (d, 1H), 6.73 (t, 1H), 6.82 (s,
1H, 15a-H), 6.95 (t, 1H), 7.02 (d, 1H), 7.20-7.35 (m, 2H), 7.54 (t,
1H), 7.77 (d, 1H), 7.94 (br s, 1H, exchangeable with deuterium
oxide), 8.36 (br s, 1H, exchangeable with deuterium oxide),
H N O ·H O: C, 60.00; H, 5.26; N,
19 18 6 2 2
1
5a-Ethyl-5,5a-dihydrobenzimidazo[1,2-a][1,3,3a ,4,6]pentaaza-
acephenanthrylene-6(7H,14aH)-one (9).
13
10.62 (s, 1H, exchangeable with deuterium oxide); C nmr: δ
66.90 (C-15a), 109.41, 112.31, 115.60, 118.30, 120.74, 121.45,
123.07, 130.44, 131.76, 132.61, 137.87, 143.61, 149.98, 154.39,
A) From 2-amino-4-(2-aminophenyl)-3,4-dihydro-1,3,5-triazino-
[1,2-a]benzimidazole (5).
+
154.68; ms (m/z, %): 304 (M , 15), 146 (100).
A stirred suspension of compound 5 (0.30 g, 1.08 mmol) and
2-ketobutyric acid (0.111 g, 1.08 mmol) in absolute ethanol (30
mL) was refluxed for 48 hours. After cooling, the solid was col-
lected, washed with chloroform and recrystallized from N,N-
Anal. Calcd. for C
Found: C, 62.89; H, 4.34; N, 27.05.
H N O: C, 63.16; H, 3.95; N, 27.36.
16 12 6
1
5,5a-Dihydrobenzimidazo[1,2-a][1,3,3a ,4,6]pentaazaace-
phenanthrylene-6(7H,14aH)-one (7a).
dimethylformamide to give 0.141 g (38% yield) of pure 9, white
-1
solid, mp 279-281 °C dec; ir (cm ): ν
3283, 1710, 1620,
A stirred suspension of compound 5 (0.30 g, 1.08 mmol) and
glyoxylic acid monohydrate (0.085 g, 0.92 mmol) in ethanol (50
mL) was refluxed for 24 hours. The hot suspension was filtered
and the solid was collected and washed with ethanol to afford
MAX
1
1518, 1293, 1201, 1174, 999, 740, 651; H nmr: δ 0.91 (t, 3H,
CH ), 1.90-2.19 (m, 2H, CH ), 6.24 (d, 1H), 6.49 (t, 1H), 6.82 (d,
3
2
1H), 7.06-7.13 (m, 2H, Ar-H + 4-H at 7.10), 7.19-7.30 (m, 2H),
7.40 (br s, 1H, exchangeable with deuterium oxide), 7.50-7.57
(m, 1H), 7.60-7.65 (m, 1H), 12.34 (br s, 1H, exchangeable with
-
0.183 g (63% yield) of pure 7a, white solid, mp >300 °C; ir (cm
1
): ν
3314, 3267, 1694, 1610, 1558, 1317, 1279, 1245, 1211,
MAX
13
1
deuterium oxide); C nmr: δ 8.03 (CH CH ), 29.13 (CH CH ),
1156, 907, 883, 859, 757, 733; H nmr: δ 5.35 (s, 1H, 5a-H), 6.24
(d, 1H), 6.50 (t, 1H), 6.83-6.94 (m, 2H), 7.07 (s, 1H, 14a-H),
7.09-7.25 (m, 3H, 1H exchangeable with deuterium oxide), 7.50-
3
2
3
2
61.98 (C-14a), 76.55 (C-5a), 109.76, 115.51, 118.35 (2C),
120.61, 122.82 (2C), 123.85, 130.44, 133.08, 141.53, 141.90,
149.69, 159.43, 176.13; ms (m/z, %): 344 (M , 46), 159 (100).
+
13
7.60 (m, 2H); C nmr: δ 62.62 (C-14a), 67.92 (C-5a), 109.43,
112.11, 115.97, 118.37, 120.70, 122.67, 123.80, 130.39, 133.08,
Anal. Calcd. for C H N O: C, 66.28; H, 4.65; N, 24.42.
19 16 6
141.57, 142.19, 150.22, 154.70, 162.44, 176.77; ms (m/z, %):
316 (M , 89), 131 (100).
Found: C, 66.67; H, 4.59; N, 24.81.
+
B) From [2-(2-Amino-3,4-dihydro-1,3,5-triazino[1,2-a]benzimi-
dazol-4-yl)phenylimino]butyric acid (8).
Anal. Calcd. for C
H N O: C, 64.55; H, 3.80; N, 26.58.
17 12 6
Found: C, 64.21; H, 4.20; N, 26.88.
A stirred suspension of compound 8 (0.07 g, 0.18 mmol) in
absolute ethanol (30 mL) was refluxed for 48 hours. The warm
suspension was filtered to remove some unreacted 8 and the fil-
trate was concentrated to a small volume under vacuum. The
solid that precipitated was collected and washed with chloroform
to give 0.037 g (59% yield) of pure 9.
1
5a-Methyl-5,5a-dihydrobenzimidazo[1,2-a][1,3,3a ,4,6]penta-
azaacephenanthrylene-6(7H,14aH)-one (7b).
A stirred solution of compound 5 (0.30 g, 1.08 mmol) and pyru-
vic acid (0.08 mL, 1.13 mmol) in absolute ethanol (30 mL) was
refluxed for 2 hours. After cooling, the solid precipitate was col-

1422
G. Primofiore, F. Da Settimo, G. Pardi, F. Simorini, C. La Motta, S. Salerno, S. Taliani
and A. M. Marini
Vol. 42
[3] A. Da Settimo, F. Da Settimo, A. M. Marini, G. Primofiore, S.
Salerno, G. Viola, L. Dalla Via and S. Marciani Magno, Eur. J. Med.
Chem., 33, 685 (1998).
[4] L. Dalla Via, O. Gia, S. Marciani Magno, A. Da Settimo, A.
M. Marini, G. Primofiore, F. Da Settimo and S. Salerno, Il Farmaco, 56,
159 (2001).
[5] L. Dalla Via, O. Gia, S. Marciani Magno, A. Da Settimo, G.
Primofiore, F. Da Settimo, F. Simorini and A. M. Marini, Eur. J. Med.
Chem., 37, 475 (2002).
Acknowledgment.
This work was supported by grants from MIUR (Research
fund Cofin 2002, ex 40%).
REFERENCES AND NOTES
*
To whom correspondence should be addressed. E-mail:
simorini@farm.unipi.it; Tel: +39-050-2219555; Fax: +39-050-2219605.
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