Dipyrrolo[1,2-a:1',2'-c]quinazoline, a new ring system of biological interest

Article abstract of DOI:10.3987/com-00-8960

Dipyrrolo[1,2-a:1',2'-c]quinazoline derivatives (10a-c) and (11b,c) were obtained in moderate to good yields by trifluoromethanesulfonic acid catalyzed decomposition of 2-(3-azidophenyl)- 1-(1H-pyrrol-2-yl)pyrroles (8a-c), through cyclisation of the protosolvated intermediates arylnitrenium ions (9).

Full text of DOI:10.3987/com-00-8960

HETEROCYCLES, Vol. 53, No. 9, 2000, pp. 1975 - 1985, Received, 29th May, 2000
DIPYRROLO[1,2-a:1',2'-c]QUINAZOLINE, A NEW RING SYSTEM OF
BIOLOGICAL INTEREST§
Francesco Mingoia,a Patrizia Diana,b Paola Barraja,b Antonino Lauria,b and
Anna Maria Almericob*
aIstituto di Chimica e Tecnologia dei Prodotti Naturali - CNR, Via Ugo La Malfa
b
153, 90146 Palermo, Italy Dipartimento Farmacochimico, Tossicologico e
Biologico - Università degli Studi, Via Archirafi 32, 90123 Palermo, Italy
Abstract - Dipyrrolo[1,2-a:1',2'-c]quinazoline derivatives (10a-c) and (11b,c)
were obtained in moderate to good yields by trifluoromethanesulfonic acid
catalyzed decomposition of 2-(3-azidophenyl)-1-(1H-pyrrol-2-yl)pyrroles (8a-c),
through cyclisation of the protosolvated intermediates arylnitrenium ions (9).
DNA represents one of the most important molecular cellular targets of several anticancer drugs.
Molecular planarity shape is a structural feature commonly required for the DNA-intercalating agents,1
which are able to insert between the stacked base paired oligonucleotides. Increasing interest towards the
phenanthridine portion, which has been proposed as an effective pharmacophore in the classes of DNA-
interactive compounds2 and the current clinical success of natural fagaridine,3 a benzo[c]phenanthridine
alkaloid, has drawn considerable attention on the synthesis4 and the biological evaluation of related
compounds.5
As part of our research program aimed to develop new polycyclic molecules through 1-heteroaryl-
pyrroles as key intermediates, and to explore their biological properties, we became interested in the
synthesis of the new ring system dipyrrolo[1,2-a:1',2'-c]quinazoline (DPQ) as bioisoster of pyrrolo[1,2-f]-
phenanthridines (PPH), which showed in vitro antiproliferative activity against cell lines derived from
human tumors in the range 5-50 µM6 and an in vitro anti-HIV-1 activity at noncytotoxic concentrations
for MT-4 cells. In particular, amino-methoxy-PPH derivatives proved a moderate but selective anti-HIV-1
activity (targeting the reverse transcriptase) coupled with a stimulation of the multiplication of T
lymphocytes.
On the basis of these premises we planned the synthesis of the title compounds and of other related
polycondensed heterocycles following a synthetic pathway involving arylnitrenium intermediates of type

(1), analogues of intermediates (2) and (3) successfully utilized for the preparation of substituted PPH,7,8
which also had the advantage of introducing an amino group in crucial position for a better DNA-
intercalation.2
R
O
Me
R2
O
N
X-
R1
N
HO
Me
OMe
PPH
fagaridine
HN
HN
N
N
N
Het
NH
OMe
1
2
3
In the case of intermediate (2), the cyclization did take place only in the presence of an activating
methoxy group in the suitable position on the N-linked ring. Such an intermediate, as π-carbocation,
needs a sufficient high electron density of the attacking substrates under the reaction conditions. In the
intermediate of type (3), the same electronic effects exerted by the the pyrrole nitrogen enhanced the
electrophilic character of the π-carbocation allowing the cyclization even in the absence of a methoxy
group. It has to be expected that the intermediate arylnitrenium ion of type (1), in which an electron rich
five membered heterocycle replaced the activated 1-phenyl substituent of (2), can result more prone to the
cyclization reaction.
The synthesis started from the opportune substituted 2-(3-azidophenyl)-1-(1H-pyrrol-2-yl)pyrroles (8)
which were easily obtained as shown in Scheme 1. Reaction of 1,4-diketone (5) with 2-amino-3-
cyanopyrroles (4a-c) in acetic acid at reflux for 4-8 h, afforded the 2-(3-nitrophenyl)pyrroles (6a-c) in
moderate to good yield (65-94%). Catalytic reduction of the nitro group at room temperature over
palladium on charcoal, produced the amino compounds (7a-c), which were treated with sodium nitrite in
acid solution followed by addition of an excess of sodium azide to give the 2-(3-azidophenyl)pyrroles
(8a-c) in good yields (81-98%). The structure of these compounds was confirmed by spectroscopic data.
In fact, the IR spectra showed bands at ca. 2110, 2224 and 3200 cm-1, due to N3, CN, and NH
respectively. The NMR spectra, in addition to all the other expected signals, exhibited a signal at 12.25-
12.86 δ, exchangeable with D2O, relative to N-H.

Scheme 1
R1
CN
CN
R1
R
Me
NH2
R
N
N
H
N
H
COOEt
4 a-c
+
COOEt
Me
O2N
NO2
6 a-c
O O
5
Red
R1
CN
R1
CN
Me
Me
HNO2/NaN3
R
N
N
H
COOEt
R
N
N
H
COOEt
N3
8 a-c
7 a-c
NH2
TFMSA
CN
R1
Me
R1
CN
R
Me
N
N
H
COOEt
R
N
N
COOEt
H
+
H2N
OH
NH
9 a-c
12 c
R1
CN
R1
CN
6
5
Me
Me
3
R
7
2
N
R
N
N
N
COOEt
COOEt
9
1
H2N
12
10
11
NH2
11 b, c
10 a-c
a: R = H, R1 = Ph; b: R = R1 = Me; c: R = Ph, R1 = Me.

The azido derivatives (8a-c) were decomposed in dichloromethane solution by treatment with a two fold
excess of trifluoromethanesulfonic acid (TFMSA) from 0 °C to room temperature. From the reaction
mixture, it was possible to isolate the 11- and 9-amino-dipyrrolo[1,2-a:1',2'-c]quinazolines of type (10)
and (11), in moderate to good overall yields. As expected, in fact, the electronic effect that the pyrrole
nucleus exerts in the intermediate protosolvated arylnitrenium ions of type (9) makes the 1-pyrrolyl
moiety nucleophilic enough to allow the cyclization even in the strong acid media. Steric effects play a
minor role with this aryl π-carbocation since it was possible to isolate even the derivatives (11b,c)
originated from cyclization in the ortho position. In the case of (8c) a little amount of the hydroxyphenyl
derivative of type (12) was also isolated, probably due to the competing intermolecular nucleophilic
reactions with triflate or water, as already observed in previous reports.7,8 In the case of the azide (8a), the
fact that was only isolated the 11-amino derivative in low yield has probably to be ascribed to the fact that
a pyrrole moiety unsubstituted at the α-position undergoes extensive decomposition under the strong acid
reaction conditions.
All structures were confirmed by IR, NMR, MS spectroscopies and elemental analysis. The comparison
of the 1H NMR data with those of other related compounds already described,7-10 and the use of additivity
rules for the effect of the substituents allowed us to assign the resonances of all the protons. In particular
it is possible to evidence, in the case of derivatives of type (10), a moderate downfield shift (0.2 - 0.4
ppm) of the resonances attributable to H-9 and H-12, this last further deshielded (up to 0.6 ppm) in
compounds (11), with respect to the chemical shifts of the protons in the amines (7). Moreover, the H-2
of the pyrrolyl moiety in compound (7a, R = H), becomes H-7 in (10a, R = H), experienced the largest
shift (~ 1.2 ppm) following the ring closure to the polycyclic ring system.
To investigate the potential ability of DPQ compounds of types (10) and (11) to interact with DNA, we
run structure optimization in vacuo by using PIMMS V1.47 and VAMP V6.1 softwares supplied by
Oxford Molecular.11 Preliminary results show that the DPQ ring system can be regarded as a
pharmacophore as shown by the good fitting between derivative (10b) and PPH or fagaridine (R.M.S. in
the range 0.0039 – 0.0109).
In summary this synthetic method involving the acid decomposition of suitable 2-(3-azidophenyl)-1-(1H-
pyrrol-2-yl)pyrroles represents a convenient access to 9-amino and/or 11-aminodipyrrolo[1,2-a:1',2'-c]-
quinazoline in yields depending on the nature of the substituents on the 1-pyrrolyl moiety. The new ring
system seems to possess all the requisite for DNA-interaction.
EXPERIMENTAL
All melting points were taken on a Büchi-Tottoli capillary apparatus and are uncorrected; IR spectra were
1
13
determined in bromoform with a JASCO FT/IR 5300 spectrophotometer; H and C NMR spectra were

measured at 200 and 50.3 MHz respectively in DMSO-d6 solution, using a Bruker AC-E series 200 MHz
spectrometer (TMS as internal reference); MS spectra were obtained with a HP 5890 Series II and HP
5989A GC/MS apparatus. Column chromatography was performed with Merck silica gel 230-400 Mesh
ASTM.
Substituted 2-aminopyrroles (4a-c)12-14 and ethyl 1-(3-nitrophenacyl)-1,4-pentandione-3-carboxylate 58
were prepared according to literature procedure.
General method for the preparation of 4,5-disubstituted ethyl 1-(3-cyanopyrrol-2-yl)-2-methyl-5-(3-
nitrophenyl)pyrrole-3-carboxylate (6a-c).
A solution of ethyl 1-(3-nitrophenacyl)-1,4-pentanedione-3-carboxylate (5) (4.4 g 15 mmol) and
aminopyrrole (4a-c) (15 mmol) in acetic acid (50 mL) was heated under reflux for 6 h. After cooling, the
resultant brown mixture was poured onto ice-water. The solid formed was filtered off, air dried, purified
by column chromatography (eluant dichloromethane), and recrystallized from ethanol.
Ethyl 1-(3-cyano-4-phenylpyrrol-2-yl)-2-methyl-5-(3-nitrophenyl)pyrrole-3-carboxylate (6a): yield 65%,
1
mp 215°C; 3225 (NH), 2222 (CN), 1672 (CO), 1529 and 1346 (NO2) cm-1; H δ 1.33 (t, J = 7.1 Hz, 3H,
CH3), 2.44 (s, 3H, CH3), 4.28 (q, J = 7.1 Hz, 2H, CH2), 7.09 (s, 1H, pyrrole H-4), 7.31 (dt, J = 7.8, 1.9 Hz,
1H, H-6'), 7.44 (t, J = 7.8 Hz, 1H, H-5'), 7.53 (s, 1H, pyrrole H-5'), 7.55-7.72 (m, 5H, C6H5), 7.79 (d, J =
1.9 Hz, 1H, H-2'), 8.08 (dt, J = 7.8, 1.9 Hz, 1H, H-4'), 11.99 (s, 1H, NH); 13C 11.45 (q), 14.33 (q), 59.59
(t), 111.41 (d), 113.77 (d), 116.79 (s), 120.37 (d), 121.92 (d), 125.30 (s), 125.80 (d), 127.29 (d), 128.92
(d), 128.93 (s), 130.25 (d), 131.39 (s), 131.84 (s), 132.01 (s), 132.24 (s), 132.26 (s), 132.95 (d), 139.96
(s), 147.80 (s), 163.76 (s); MS: m/z 440 (M+). Anal. Calcd for C25H20N4O4: C, 68.17; H, 4.58; N, 12.72.
Found: C, 68.30 ; H, 4.56; N, 13.10.
Ethyl 1-(3-cyano-4,5-dimethylpyrrol-2-yl)-2-methyl-5-(3-nitrophenyl)pyrrole-3-carboxylate (6b): yield
1
90%, mp 203-204°C; 3248 (NH), 2232 (CN), 1703 (CO), 1533 and 1348 (NO2) cm-1; H δ 1.34 (t, J =
6.7 Hz, 3H, CH3), 2.05 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.46 (s, 3H, CH3), 4.29 (q, J = 6.7 Hz, 2H, CH2),
7.09 (s, 1H, pyrrole H-4), 7.57 (dt, J = 7.3, 1.2 Hz, 1H, H-6'), 7.64 (t, J = 7.3 Hz, 1H, H-5'), 7.84 (d, J =
13
1.2 Hz, 1H, H-2'), 8.09 (dt, J = 7.3, 1.2 Hz, 1H, H-4'), 12.35 (s, 1H, NH); C 9.31 (q), 10.26 (q), 11.47
(q), 14.31 (q), 59.57 (t), 91.75 (s), 111.28 (d), 113.61 (s), 114.48 (s), 116.41 (s), 120.46 (d), 121.71 (d),
124.88 (s), 127.05 (s), 130.08 (d), 132.01 (s), 132.51 (s), 132.76 (d), 140.16 (s), 147.89 (s), 163.87 (s);
MS: m/z 392 (M+). Anal. Calcd for C21H20N4O4: C, 64.28; H, 5.14; N, 14.28. Found: C, 64.02; H, 5.15;
N, 14.33.

Ethyl 1-(3-cyano-4-methyl-5-phenylpyrrol-2-yl)-2-methyl-5-(3-nitrophenyl)pyrrole-3-carboxylate (6c):
yield 94%, mp 203-205°C; 3231 (NH), 2216 (CN), 1678 (CO), 1533 and 1346 (NO2) cm-1; 1H: δ 1.33 (t,
J = 7.1 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 2.48 (s, 3H, CH3), 4.29 (q, J = 7.1 Hz, 2H, CH2), 7.11 (s, 1H,
pyrrole H-4), 7.30-7.79 (m, 5H, C6H5), 7.43 (d, J = 8.2 Hz, 1H, H-6'), 7.63 (t, J = 8.2 Hz, 1H, H-5'), 7.82
(s, 1H, H-2'), 8.09 (d, J = 8.2 Hz, 1H, H-4'), 12.94 (s, 1H, NH); 13C 10.94 (q), 11.60 (q), 14.34 (q), 59.64
(t), 93.64 (s), 111.43 (d), 113.86 (s), 114.05 (s), 117.79 (s), 120.51 (d), 121.83 (d), 127.25 (d), 127.59 (d),
128.63 (s), 128.82 (d), 129.22 (s), 130.17 (d), 130.82 (s), 132.19 (s), 132.47 (s), 133.02 (s), 140.21 (d),
147.87 (s), 163.88 (s); MS: m/z 454 (M+). Anal. Calcd for C26H22N4O4: C, 68.71; H, 4.88; N, 12.33.
Found: C, 68.84; H, 4.86; N, 12.37.
General method for the preparation of 4,5-disubstituted ethyl 5-(3-aminophenyl)-1-(3-cyano-
pyrrol-2-yl)-2-methylpyrrole-3-carboxylate (7a-c).
A solution of nitro derivatives (6a-c) (8 mmol) in ethanol (50 mL) was reduced overnight with hydrogen
over 10% Pd on charcoal (0.1 g) in a Parr apparatus at 50 psi at rt. Removal of the catalyst and
evaporation of the solvent under reduced pressure gave the amino derivatives (7a-c) which were purified
by recrystallization from ethanol.
Ethyl 5-(3-aminophenyl)-1-(3-cyano-4-phenylpyrrol-2-yl)-2-methylpyrrole-3-carboxylate (7a) yield 91%,
1
mp 217°C; 3425 and 3358 (NH2), 3213 (NH), 2226 (CN), 1651 (CO) cm-1; H δ 1.31 (t, J = 6.8 Hz, 3H,
CH3), 2.39 (s, 3H, CH3), 4.26 (q, J = 6.8 Hz, 2H, CH2), 5.10 (s, 2H, NH2), 6.18 (d, J = 7.6 Hz, 1H, H-4'),
6.46 (d, J = 7.6 Hz, 1H, H-6'), 6.58 (s, 1H, H-2'), 6.67 (s, 1H, pyrrole H-4), 6.90 (t, J = 7.6 Hz, 1H, H-5'),
7.30 (t, J = 6.8 Hz, 1H, H-4''), 7.43 (t, J = 7.6 Hz, 2H, H-3'' and H-5''), 7.45 (s, 1H, pyrrole H-5'), 7.67 (d,
13
2H, J = 7.6 Hz, H-2'' and H-6''), 12.76 (s, 1H, NH); C 11.38 (q), 14.36 (q), 59.38 (t), 88.62 (s) 108.85
(d), 112.79 (d), 113.10 (s), 113.27 (d), 113.92 (d), 115.10 (s), 116.13 (d), 124.75 (s), 125.67 (d), 127.12
(d), 128.89 (d), 128.90 (d), 131.46 (s), 132.53 (2s), 135.64 (s), 138.44 (s), 148.76 (s), 164.10 (s); MS: m/z
410 (M+). Anal. Calcd for C25H22N2O2: C, 73.15; H, 5.40; N, 13.65. Found: C, 73.36; H, 5.42; N, 13.67.
Ethyl 5-(3-aminophenyl)-1-(3-cyano-4,5-dimethylpyrrol-2-yl)-2-methylpyrrole-3-carboxylate (7b): yield
70%, mp 208-210°C; 3375 and 3275 (NH2), 3189 (NH), 2214 (CN), 1692 (CO) cm-1; 1H δ 1.30 (t, J = 7.0
Hz, 3H, CH3), 2.01 (s, 3H, CH3), 2.10 (s, 3H, CH3) 2.30 (s, 3H, CH3), 4.23 (q, J = 7.0 Hz, 2H, CH2), 5.0 7
(s, 2H, NH2), 6.11 (d, J = 7.3 Hz, 1H, H-4'), 6.44 (d, 1H, J = 7.3 Hz, H-6'), 6.53 (s, 1H, H-2'), 7.09 (s, 1H,
pyrrole H-4), 6.88 (t, J = 7.3 Hz, 1H, H-5'), 12.05 (bs, 1H, NH); 13C 9.43 (q), 10.34 (q), 11.36 (q), 14.37
(q), 59.30 (t), 91.28 (s), 108.63 (d), 112.70 (d), 112.72 (s), 113.13 (d), 113.82 (d), 114.89 (s), 115.79 (s),

124.02 (s), 128.07 (s), 128.81 (d), 131.56 (s), 135.50 (s), 138.56 (s), 148.70 (s) 164.12 (s); MS: m/z 362
(M+). Anal. Calcd for C21H22N4O2: C, 69.59; H, 6.12; N, 15.46. Found: C, 69.52; H, 6.10; N, 15.86.
Ethyl 5-(3-aminophenyl)-1-(3-cyano-4-methyl-5-phenylpyrrol-2-yl)-2-methylpyrrole-3-carboxylate (7c):
yield 90%, mp 215-216°C; 3373 and 3275 (NH2), 3192 (NH), 2218 (CN), 1695 (CO) cm-1; 1H δ 1.31 (t, J
= 6.9 Hz, 3H, CH3), 2.27 (s, 3H, CH3), 2.40 (s, 3H, CH3), 4.25 (q, J = 6.9 Hz, 2H, CH2), 5.10 (s, 2H,
NH2), 6.22 (d, J = 7.6 Hz, 1H, H-4'), 6.47 (d, J = 7.6 Hz, 1H, H-6'), 6.59 (s, 1H, H-2'), 6.66 (s, 1H, pyrrole
H-4), 6.90 (t, J = 7.6 Hz, 1H, H-5'), 7.33 (t, 1H, J = 7.6 Hz, H-4''), 7.46 (t, J= 7.6 Hz, 2H, H-3'' and H-5''),
7.52 (d, J = 7.6 Hz, 2H, H-2'' and H-6''), 12.65 (s, 1H, NH); 13C 11.18 (q), 11.52 (q), 14.40 (q), 59.40 (t),
93.31 (s), 108.83 (d), 112.86 (d), 113.03 (s), 113.28 (d), 114.07 (d), 114.43 (s), 117.34 (s), 127.02 (d),
127.34 (d), 127.76 (s), 128.81 (d), 128.87 (d), 130.32 (s), 130.92 (s), 131.59 (s), 135.73 (s), 138.56 (s),
148.76 (s), 164.17 (s); MS: m/z 424 (M+). Anal. Calcd for C26H24N4O2: C, 73.57; H, 5.70; N, 13.20.
Found: C, 73.27; H, 5.68; N, 13.25.
General method for the preparation of 4,5-disubstituted ethyl 5-(3-azidophenyl)-2-methyl-1-(3-
cyanopyrrol-2-yl)pyrrole-3-carboxylate (8a-c).
To a solution of the amines (7a-c) (10 mmol) in acetic acid (20 mL) sodium nitrite (690 mg, 10 mmol) in
water (20 mL) was added at 0-5°C. After stirring for 1 h sodium azide (1.3 g, 20 mmol) in small portions
was added at rt. The reaction mixture was stirred for further 24 h at rt and then poured onto crushed
ice/water. The solid was filtered off, air dried and recrystallized from ethanol.
Ethyl 5-(3-azidophenyl)-1-(3-cyano-4-phenylpyrrol-2-yl)-2-methylpyrrole-3-carboxylate (8a): yield 98%,
mp 173-175°C; 3202 (br NH), 2222 (CN), 2099 (N3), 1672 (CO) cm-1; 1H δ 1.32 (t, J = 7.1 Hz, 3H, CH3),
2.43 (s, 3H, CH3), 4.28 (q, J = 7.1 Hz, 2H, CH2), 6.75 (s, 1H, H-2’), 6.95 (s, 1H, pyrrole H-4), 6.97 (d, J =
8.3 Hz, 1H, H-4'), 7.05 (d, J = 8.3 Hz, 1H, H-6'), 7.31 (t, J = 8.3 Hz, 1H, H-5'), 7.33 (t, J = 7.6 Hz, 1H, H-
4''), 7.44 (t, J = 7.6 Hz, 2H, H-3'' and H-5''), 7.51 (s, 1H, pyrrole H-5'), 7.65 (d, J= 7.6 Hz, 2H, H-2'' and
13
H-6''), 12.87 (bs, 1H, NH); C (ppm): 11.38 (q), 14.36 (q), 59.38 (t), 88.62 (s) 108.85 (d), 112.79 (d),
113.10 (s), 113.27 (d), 113.92 (d), 115.10 (s), 116.13 (d), 124.75 (d), 125.67 (d), 127.11 (s), 128.89 (d),
131.46 (s), 132.53 (s), 135.64 (s), 138.44 (s), 148.76 (s), 132.95 (d), 139.96 (s), 147.80 (s), 164.10 (s);
MS: m/z 410 (M+-26). Anal. Calcd for C25H20N6O2: C, 68.79; H, 4.62; N, 19.26. Found: C, 68.99; H,
4.68; N, 19.27.
Ethyl 5-(3-azidophenyl)-1-(3-cyano-4,5-dimethylpyrrol-2-yl)-2-methylpyrrole-3-carboxylate (8b): yield
1
81%, mp 188-190°C; 3173 (NH), 2218 (CN), 2105 (N3), 1664 (CO) cm-1; H δ 1.31 (t, J = 7.1 Hz, 3H,

CH3), 2.02 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.36 (s, 3H, CH3), 4.26 (q, J = 7.1 Hz, 2H, CH2), 6.61 (brs, 1H,
H-2'), 6.92 (s, 1H, pyrrole H-4), 6.94 (d, J = 7.9 Hz, 1H, H-4'), 7.09 (d, 1H, J = 7.9 Hz, H-6'), 7.34 (t, J =
13
7.9 Hz, 1H, H-5'), 12.25 (bs, 1H, NH); C 9.37 (q), 10.31 (q), 11.42 (q), 14.36 (q), 59.47 (t), 91.54 (s),
110.23 (d), 113.23 (s), 114.54 (s), 115.71 (d), 116.27 (s), 118.04 (d), 123.41 (d), 124.56 (s), 127.41 (s),
130.25 (d), 132.63 (s), 133.09 (s), 139.45 (s), 139.54 (s) 169.18 (s); MS: m/z 362 (M+-26). Anal. Calcd
for C21H20N6O2: C, 64.94; H, 5.19; N, 21.64. Found: C, 64.74; H, 5.20; N, 21.72.
Ethyl 5-(3-azidophenyl)-1-(3-cyano-4-methyl-5-phenylpyrrol-2-yl)-2-methylpyrrole-3-carboxylate (8c):
yield 86%, mp 170-172°C; 3225 (NH), 2224 (CN), 2105 (N3), 1672 (CO) cm-1; 1H: δ 1.32 (t, J = 7.1 Hz,
3H, CH3), 2.27 (s, 3H, CH3), 2.45 (s, 3H, CH3), 4.28 (q, J = 7.1 Hz, 2H, CH2), 6.72 (br s, 1H, H-2'), 6.90-
6.99 (m, 2H, H-4' and pyrrole H-4), 7.12 (d, 1H, J = 7.5 Hz, H-6'), 7.30-7.40 (m, 2H, H-5' and H-4''),
13
7.41-7.58 (m, 4H, H-2'', H-3'', H-5'', and H-6''), 12.80 (s, 1H, NH); C 11.07 (q), 11.53 (q), 14.37 (q),
59.52 (t), 93.40 (s), 110.38 (d), 113.46 (s), 114.11 (s), 116.03 (d), 117.60 (s), 118.14 (d), 123.54 (d),
127.05 (d), 127.34 (s), 127.50 (d), 128.19 (s), 128.82 (d), 129.60 (s), 130.28 (d), 130.68 (s), 132.60 (s),
133.28 (s), 139.50 (s), 163.94 (s); MS m/z 424 (M+-26). Anal. Calcd for C26H22N6O2: C, 69.32; H, 4.92;
N, 18.65. Found: C, 69.52; H, 4.89; N, 18.68.
Decomposition of the azido compounds (8a-c) in TFMSA.
To a solution of the azido derivatives (8a-c) (6 mmol) in dry dichloromethane (50 mL)
trifluoromethanesulfonic acid (1.8 g, 12 mmol) was added dropwise at 0°C. The reactants were allowed to
stand at rt and stirred for further 24 h. The reaction mixture was evaporated under reduced pressure,
treated with a saturated solution of sodium bicarbonate (150 mL), and extracted with dichloromethane (4
x 100 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give a
brown residue which was chromatographed.
In the case of the decomposition of derivative (8a) elution with dichloromethane/ethyl acetate (95:05)
gave ethyl 11-amino-5-cyano-3-methyl-6-phenyldipyrrolo[1,2-a:1',2'-c]quinazoline-2-carboxylate (10a)
(30%), which was recrystallized from ethanol, mp 213-214°C; 3474 and 3354 (NH2), 2226 (CN), 1688
1
(CO) cm-1; H δ 1.38 (t, J = 6.9 Hz, 3H, CH3), 2.82 (s, 3H, CH3), 4.28 (q, J = 6.9 Hz, 2H, CH2), 5.59 (s,
2H, NH2), 6.38 (dd, J = 7.2, 1.3 Hz, 1H, H-10), 6.78 (d, J = 8.7 Hz, 1H, H-9), 7.00 (d, J = 1.3 Hz, 1H, H-
12), 7.06 (s, 1H, H-1), 7.48-7.58 (m, 3H, H-3, H-4' and H-5'), 7.81 (dd, J = 7.7, 1.0 Hz, 2H, H-2' and H-
13
6'), 7.90 (s, 1H, H-7); C 12.01 (q), 14.23 (q), 59.86 (t), 108.45 (d), 109.71 (d), 110.66 (s), 113.09 (d),
116.12 (s), 116.83 (s), 126.55 (d), 126.88 (d), 127.72 (s), 128.97 (d), 129.33 (d), 129.65 (s), 131.03 (s),

132.88 (s), 136.43 (s), 143.64 (d), 150.49 (2s), 162.35 (s), 163.41 (s); MS: m/z 408 (M+). Anal. Calcd for
C25H20N4O2: C, 73.51; H, 4.94; N, 13.72. Found: C, 73.33; H, 4.96; N, 13.75.
In the case of the decomposition of derivative (8b) elution with dichloromethane/ethyl acetate (95:05)
gave a first fraction (25%) which was identified as a mixture (5:1) of (10b) and ethyl 9-amino-5-cyano-
3,6,7-trimethyldipyrrolo[1,2-a:1',2'-c]quinazoline-2-carboxylate (11b): 1H δ 1.06 (t, J = 7.0 Hz, 3H, CH3),
2.15 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.84 (s, 3H, CH3), 4.32 (q, J = 7.0 Hz, 2H, CH2), 5.51 (s, 2H, NH2),
6.61 (dd, J = 8.4, 1.5 Hz, 1H, H-10), 6.96 (s, 1H, H-1), 6.98-7.00 (m, 1H, H-11), 7.22 (dd, J = 8.4, 1.5 Hz,
1H, H-12); MS: m/z 360 (M+).
Further elution with dichloromethane/ethyl acetate (95:05) gave ethyl 11-amino-5-cyano-3,6,7-
trimethyldipyrrolo[1,2-a:1',2'-c]quinazoline-2-carboxylate (10b) (40%), which was recrystallized from
1
1
-
ethanol, mp 168-170°C; 3482 and 3399 (NH ), 2226 (CN), 1688 (CO) cm ; H δ 1.32 (t, J = 7.0 Hz, 3H,
2
CH3), 2.15 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.78 (s, 3H, CH3), 4.26 (q, J = 7.0 Hz, 2H, CH2), 5.56 (s, 2H,
NH2), 6.56 (dd, J = 8.5, 1.9 Hz, 1H, H-10), 6.96 (s, 1H, H-1), 7.00 (d, J = 1.9 Hz, 1H, H-12), 7.35 (d, J =
8.5 Hz, 1H, H-9); 13C 10.99 (q), 12.06 (q), 12.84 (q), 14.22 (q), 59.78 (t), 107.70 (d), 109.79 (d), 111.74
(s), 113.90 (d), 114.53 (s), 115.28 (s), 115.92 (s), 121.87 (s), 126.61 (d), 126.99 (s), 129.76 (s), 136.00
(s), 150.25 (s), 151.19 (s), 159.97 (s), 163.52 (s); MS: m/z 360 (M+). Anal. Calcd for C21H20N4O2: C,
69.98; H, 5.59; N, 15.55. Found: C, 69.84; H, 5.57; N, 15.61.
In the case of the decomposition of derivative (8c) elution with dichloromethane/ethyl acetate (95:05)
gave ethyl 9-amino-5-cyano-3,6-dimethyl-7-phenyldipyrrolo[1,2-a:1',2'-c]quinazoline-2-carboxylate
(11c) (10%), which was recrystallized from ethanol, mp 111-113°C; 3461 and 3383 (NH2), 2222 (CN),
1691 (CO) cm-1; 1H δ 1.27 (t, J = 7.2 Hz, 3H, CH3), 2.18 (s, 3H, CH3), 2.63 (s, 3H, CH3), 4.18 (q, J = 7.2
Hz, 2H, CH2), 4.66 (s, 2H, NH2), 6.58 (d, J = 8.2 Hz, 1H, H-10), 6.67 (s, 1H, H-1), 6.92 (d, J = 8.2 Hz,
1H, H-12), 7.19 (t, J = 8.2 Hz, 1H, H-11), 7.50-7.66 (m, 3H, H-3', H-4', and H-5'), 7.95-8.00 (m, 2H, H-2'
and H-6'); 13C 9.54 (q), 14.34 (q), 15.21 (q), 59.12 (t), 95.39 (s), 100.43 (d), 108.08 (d), 112.50 (s), 115.09
(d), 116.06 (s), 116.48 (s), 126.38 (s), 128.68 (d), 128.85 (d), 131.31 (d), 131.57 (s), 131.80 (d), 133.56
(s), 133.66 (s), 136.02 (s), 143.79 (s), 156.52 (s), 164.24 (s), 175.23 (s); MS: m/z 422 (M+). Anal. Calcd
for C26H22N4O2: C, 73.92; H, 5.25; N, 13.26. Found: C, 73.69; H, 5.23; N, 13.31.
Further elution with dichloromethane/ethyl acetate (9:1) gave ethyl 5-(5-amino-2-hydroxyphenyl)-1-(3-
cyano-4-methyl-5-phenylpyrrol-2-yl)-2-methylpyrrole-3-carboxylate
(12c)
(10%),
which
was
1
-
recrystallized from ethanol, mp 169-170°C; 3499-3383 (NH2, OH, and NH), 2224 (CN), 1697 (CO) cm ;
1H δ 1.34 (t, J = 7.0 Hz, 3H, CH3), 2.61 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.60 (bs, 1H, OH), 4.28 (q, J =
7.0 Hz, 2H, CH2), 5.62 (s, 2H, NH2), 6.62 (dd, J = 8.2, 2.5 Hz, 1H, H-4'), 7.01 (s, 1H, pyrrole H-4), 7.05

(d, J = 2.5 Hz, 1H, H-6'), 7.42-7.59 (m, 4H, H-3', H-3", H-4", and H-5"), 7.79 (dd, J = 7.0, 1.2 Hz, 2H, H-
13
2" and H-6"), 12.33 (s, 1H, NH); C 12.07 (q), 12.95 (q), 14.25 (q), 59.80 (t), 107.94 (d), 109.00 (d),
111.56 (s), 113.91 (d), 115.68 (s), 116.69 (s), 122.42 (s), 126.66 (d), 127.09 (d), 128.21 (d), 128.61 (d),
129.04 (s), 129.72 (s), 132.41 (s), 136.29 (s), 150.43 (s), 151.42 (s), 160.03 (s), 163.50 (s), 171.23 (s);
MS: m/z 440 (M+). Anal. Calcd for C26H24N4O3: C, 70.89; H, 5.49; N, 12.72. Found: C, 70.74; H, 5.50;
N, 12.75.
Further elution with dichloromethane/ethyl acetate (9:1) gave ethyl 11-amino-5-cyano-3,6-dimethyl-7-
phenyldipyrrolo[1,2-a:1',2'-c]quinazoline-2-carboxylate (10c) (70%), which was recrystallized from
1
1
-
ethanol, mp 145-146°C; 3490 and 3374 (NH2), 2222 (CN), 1689 (CO) cm ; H δ 1.28 (t, J = 6.9 Hz, 3H,
CH3), 2.21 (s, 3H, CH3), 2.55 (s, 3H, CH3), 4.20 (q, J = 6.9 Hz, 2H, CH2), 5.54 (s, 2H, NH2), 6.42 (dd, J =
8.1, 1.5 Hz, 1H, H-10), 6.64 (s, 1H, H-1), 6.80 (d, J = 8.1 Hz, 1H, H-9), 6.83 (d, J = 1.5 Hz, 1H, H-12),
13
7.50-7.65 (m, 3H, H-3', H-4', and H-5'), 7.91 (d, J = 7.3 Hz, 2H, H-2' and H-6'); C 9.82 (q), 14.38 (q),
14.81 (q), 59.11 (t), 95.24 (s), 100.47 (d), 104.82 (d), 112.28 (d), 112.68 (s), 116.19 (s), 121.08 (s),
122.57 (d), 128.20 (s), 128.54 (d), 128.85 (d), 131.58 (d), 131.66 (s), 133.55 (s), 134.34 (s), 135.93 (s),
151.01 (s), 154.33 (s), 164.25 (s), 174.90 (s); MS: m/z 422 (M+). Anal. Calcd for C26H22N4O2: C, 73.92;
H, 5.25; N, 13.26. Found: C, 73.69; H, 5.23; N, 13.29.
ACKNOWLEDGEMENTS
This work was in part financially supported by Consiglio Nazionale delle Ricerche (Rome) and by
Ministero dell'Università e della Ricerca Scientifica e Tecnologica.
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§
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