A new entry to the substituted pyrrolo[3,2-c]quinoline derivatives of biological interest by intramolecular heteroannulation of internal imines

Article abstract of DOI:10.1016/j.tet.2004.05.047

New 1,3,4-substituted pyrrolo[3,2-c]quinoline derivatives were synthesised in good yields by oxidative heteroannulation of internal imines starting from easily prepared substituted 5-(2-aminophenyl)pyrroles and commercially available aryl and heteroaryl a

Full text of DOI:10.1016/j.tet.2004.05.047

Tetrahedron 60 (2004) 5873–5880
A new entry to the substituted pyrrolo[3,2-c]quinoline derivatives
of biological interest by intramolecular heteroannulation of
internal imines
Maria Luisa Testa,a Liliana Lamartinab and Francesco Mingoiaa
,
*
aIstituto per lo Studio dei Materiali Nanostrutturati, (I.S.M.N.-C.N.R.), sezione di Palermo, via Ugo La Malfa 153, 90146 Palermo, Italy
`
Dipartimento di Chimica e Tecnologie Farmaceutiche, Universita di Palermo, via Archirafi 32, 90123 Palermo, Italy
b
Received 26 September 2003; revised 30 April 2004; accepted 20 May 2004
Available online 7 June 2004
Abstract—New 1,3,4-substituted pyrrolo[3,2-c]quinoline derivatives were synthesised in good yields by oxidative heteroannulation of
internal imines starting from easily prepared substituted 5-(2-aminophenyl)pyrroles and commercially available aryl and heteroaryl
aldehydes. The reaction occurs as a one-pot process involving an intramolecular acid catalysed reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
synthetic route, so as to further investigate the interaction of
such molecules with DNA.
For many years, the pyrrolo[3,2-c]quinoline ring system (I,
Scheme 1) has been known as a core structure unit of
bioactive molecules of either synthetic1 or natural source.2
Several derivatives of such a tricyclic angular heterocycle
possess a wide spectrum of biological activities,3 including
most notably antitumor properties,4 gastric (Hþ/Kþ)-
ATPase inhibitor,5 hypotensive,6 anti-inflammatory activi-
ties7 and others. The relatively recent isolation of this
framework from the organic extracts of Martinella
iquitosensis roots, which evidenced antagonist properties
against bradykinin receptors,8 renewed interest has attracted
several research groups to plan new synthetic approaches.
The wide potential of such a skeleton along with our interest
in targets featuring nitrogen containing aromatized poly-
cyclic structures prompted us to develop an alternative
A perusal of the literature highlights a large number of
different synthetic pathways to such rings. However, only a
few convenient cases concern entirely planar aromatic ring
systems; such as those concerning the Fischer-indole
synthesis,9 metal mediated reactions,1,10 and aryl radical
cyclization onto pyrroles.11
As an extension of our ongoing work in the field directed to
the development of new synthetic approaches to polycyclic
nitrogen heterocycles,12 as well as exploration of their
biological and structural properties, we report here an
alternative and convenient pathway leading, in good yields,
to a series of new substituted pyrrolo[3,2-c]quinoline
compounds.
The retrosynthetic approach proposed is illustrated in
Scheme 1. It involves a double disconnection at the central
pyridine ring to afford the 5-(o-aminophenyl) pyrroles II,
which in turn would arise from the corresponding 1,4-
diketone III and alkyl, aryl, heteroaryl amines simply
formed by a Paal-Knorr reaction. Precursors III were easily
synthesized according to the literature procedures13,14
modified by us to achieve higher yields (see Section 4).
Such a strategy, in combination with the possibility of using
a wide range of commercially available reactants, allows
functionalization of crucial positions of the pyrrole ring and
can be suitable in combinatorial chemistry for the synthesis
of a small library.
Scheme 1. Disconnection approach of the pyrrolo[3,2-c]quinoline core.
Keywords: Pyrrolo[3,2-c]quinoline derivatives; Intramolecular
heteroannulation; Internal imines, NMR chemical shifts.
*
Corresponding author. Tel.: þ39-091-680-93-68; fax: þ39-091-680-93-
Reported synthetic pathways have mainly considered the
99; e-mail address: mingoia@pa.ismn.cnr.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.047

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M. L. Testa et al. / Tetrahedron 60 (2004) 5873–5880
construction of the pyrrolo[3,2-c]quinoline core starting
from a preformed quinoline moiety,15 fluorinated syn-
thons,16 substituted hydropyridine,17 but limitations and/or
low overall yields are often encountered. Often, the
introduction of a specific substituent, especially in position
4 of the preformed skeleton, required laborious steps
coupled with drastic experimental conditions. Moreover, it
did not appear to offer much flexibility for preparing
derivatives with groups other than simple alkyl ones in the
4 position.18
heteroaryl amines, which under reflux (3–8 h) in acetic
acid, afforded the corresponding 5-(o-nitrophenyl)-1-sub-
stitued pyrroles 2a-e in 60–87% isolated yield. Reduction
with Pd/C in a Parr apparatus furnished the amino
derivatives 3a-e, in yields from good to excellent
(Scheme 2).
Treatment of the latter amines with a slight excess of
aldehydes in the presence of 15 mol% of p-toluenesulfonic
acid (p-TsOH) in DMF at 100 8C provided compounds 4a-f
in good yields (72–94%) within 3 h.
In this case, for our target molecules, we considered
o-aminophenylpyrroles II as strategic precursors. Although,
they have proved to be very versatile key intermediates,
leading to a wide variety of pyrrolo-fused heterocycles,19–22
to our knowledge, none of the previous synthetic pathways
explored their reactivity via imine formation and intra-
molecular cyclization. The only reported example involving
a carbonyl function concerned the use of formic acid, which
in boiling benzene cyclized to the dihydro-pyrroloquinazo-
line ring.14
Such a result may be reasonably accounted for on the basis
of an intramolecular addition of pyrrole b-carbon on the
transiently formed protonated imine (IV) to give the
tricyclic intermediate (V), followed by spontaneous
dehydrogenation (Scheme 2).
Attempted isolation of the imines IV or the cycloadduct V
from the reaction as intermediates failed, even when
operating under milder reaction condition.23 Only during
GC–MS monitorage of the reaction was a trace amount of a
peak corresponding to the mass of the supposed imine IV or
the dihydro cycloadduct V detected. Probably, this fact
reflects the high reactivity of the internal nucleophile
(pyrrole C-3) which immediately evolves to the fully
aromatic system. It should be noted that isolation of the
oxidized aromatic derivatives was also observed even in
the presence of reductive condition,11 confirming that the
thermodynamic gain involved in the aromatization process
is relevant.
Here, we report our results on the development of a new and
convenient one pot access to the title ring system starting
from precursor II.
2. Results and discussion
The reaction sequence starts with the Paal-Knorr reaction
between 1,4-diketones 1a,b13,14 and commercial alkyl, aryl,
Scheme 2. General procedure for the preparation of the novel pyrroloquinoline derivatives.

M. L. Testa et al. / Tetrahedron 60 (2004) 5873–5880
5875
Scheme 3. Formation of the competitive pyrrolo[1,2-c]quinazoline ring.
It is interesting to note the key step of this sequence is
strongly related to a variant of the well-known Mannich
reaction, and in particular the Pictet-Spengler condensation,
which also features the first step on intramolecular addition
of the position 3 of an indole derivative onto an in situ
generated iminium ion.24
In an attempt to introduce heteroaryl moieties on position 1,
commercial 3-amino-5-methyl pyrazole was reacted with
triketone 1b (Scheme 4). Upon heating under reflux in acetic
acid, a major compound (60% yields) with a peak m/z of 324
in the mass spectrum was isolated from the reaction mixture.
NMR data of this product excluded the expected 1-pyrazol-
2-yl pyrrole derivative 2g. In fact, besides the signals for the
(2-nitrophenyl) group, 1H NMR spectrum showed a singlet
at dH 6.36 ppm related to one proton, with a signal for the
corresponding carbon atom at dC 94.30 ppm in the 13C
NMR spectrum, attributable to a pyrazole CH. Furthermore,
the presence of a methylene group was also evidenced by a
singlet at dH 4.57 ppm integrated for two protons in the 1H
NMR spectrum and by the corresponding carbon atom
signal at dC 41.22 ppm in the 13C NMR spectrum, confirmed
by DEPT experiments.
When the pyrroloaniline 3b was treated with PhCHO under
the same experimental conditions as before (Scheme 3), the
expected compound 4b was isolated as major product (85%)
along with traces of the cycloadduct 5,6-dihydro-
pyrrolo[1,2-c]quinazoline derivative 5 (2%) which appears
to result from competitive NH pyrrole addition on the
intermediate protonated imine.
In fact, besides the expected signals, the 1H NMR spectrum
of compound 5 exhibited a singlet at dH 6.62 ppm related to
the dihydro pyrimidine CH together with another singlet at
dH 7.06 ppm relative to the pyrrole CH. The signals for the
corresponding carbon atoms in the 13C NMR spectrum were
found at dC 65.51 and 103.81 ppm, respectively.
Usually, 1,4-diketones and 2-amino-azoles give rise to 4þ1
cyclo-condensation.12b In the case of triketone 1b, other types
of cyclo-condensation (3þ3 or 4þ3) could be envisaged.
So, compounds 6 or 7 could be formed, respectively.
Scheme 4. Competitive 3þ3 cyclo-condensation in the attempted preparation of 2g.

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M. L. Testa et al. / Tetrahedron 60 (2004) 5873–5880
Analysis of the NMR data allowed us to assign the structure
6 to the isolated product. Unequivocal assignment of the
signals was performed by 2D NMR experiments showing
both one-bond and long-range heteronuclear C–H corre-
lations. In addition to the one-bond correlation with the CH2
introduction onto position 1, 3 and 4 of the title ring system
a variety of selected functional groups, which in turn are
useful for structure–activity relationships studies or may be
susceptible of further synthetic development. Although
some limitation could be encountered, as observed for the
cyclo-condensation of 3-aminopyrazole, the ready avail-
ability of the starting materials and ease of this procedure
make this method ideal for an alternative new access to fully
aromatic pyrrolo[3,2-c]quinoline derivatives.
2
carbon atom, the methylene protons exhibited J connec-
tions with C-6 and carbonyl carbon atoms and 3J
connections with C-5 and C-7 carbon atoms. Analogously,
besides the one-bond correlations, methyl protons exhibited
2J correlations with the related C-ipso carbon atoms and 3J
correlations with the C-ortho carbon atoms. Therefore, C-6
carbon atom showed correlations with 5-Me and 7-Me
protons, whereas C-3 carbon atom correlated with 2-Me
protons. Correlations of pyrazole proton with C-2 and C-3a
quaternary carbon atoms were also detected. Finally, the
signals of the (2-nitrophenyl) group showed the appropriate
correlations either interannular and to carbonyl carbon atom.
4. Experimental
4.1. Materials and general methods
Unless otherwise specified, materials were purchased from
commercial suppliers (Aldrich) and used without further
purification. Acetic acid was distilled from acetic anhydride
(3%, w/v) under argon Analytical thin layer chromato-
graphy was performed on Merck precoated silica gel (60
F254) plates and column chromatography was accomplished
on Merck silica gel 230–400 mesh (ASTM). Melting points
were determined with a Buchi-Tottoli capillary apparatus
and are uncorrected. IR spectra were determined in bromo-
The same correlations were found in the 2D NMR spectra of
the amino derivative 8 in turn obtained by hydrogenation of
6. In this case, chemical shift variations lDdl#0.68 were
detected for 13C NMR signals of pyrazolo[1,5-a]pyrimidine
ring carbon atoms, with the exception of C-6 (Dd¼þ2.40)
and exocyclic methylene (Dd¼23.41) carbon atoms. As
expected, the (2-aminophenyl) group showed in the 1H and
13C NMR spectra the appropriate signals of the reduction
product of 6.
1
form with a Jasco FT-IR 5300 spectrometer. H and 13C
NMR spectra were recorded on a Bruker AC 250
spectrometer operating in FT mode in DMSO-d6 solutions
at 250.13 and 62.89 MHz, respectively. 1H and 13C
chemical shift values are given in ppm relative to TMS
(as internal standard) and DMSO-d6 (centered at 39.50 ppm
downfield from TMS), respectively. Coupling constants
values are in Hz. 13C chemical shift values were measured
from proton fully decoupled spectra. Signals assignment
was made on the basis both of known substituent effects and
of one-bond multiplicities (indicated in parentheses)
determined by DEPT-135 and confirmed by 2D C,H
correlation experiments, using the standard Bruker pulse
sequences XHDEPT.AUR and COLOC.AUR, for one-bond
and long-range C,H interactions, respectively. Mass spectra
(EI) were collected on a GC-MS-QP5050A Shimadzu mass
spectrometer with ionization energy of 70 eV. Elemental
analyses were performed on a Perkin–Elmer 240 8C
elemental analyzer and the results were within ^0.3% of
the theoretical values. Yields refer to purified products and
are not optimized.
Additional support was furnished by the fragmentation
pattern as pointed out in the mass spectra of compound 6, in
which the base peak fragment at m/z 174, relative to the
stable pyrazolopyrimidine scaffold, was detected (Fig. 1).
Figure 1. Base peak fragment observed at GC–MS (EI 70 eV) for
compound 6.
The above example indicates that the hetero-functionaliza-
tion onto position 1 of the ring is strictly dependent on the
nature and the reactivity of the heteroaryl amino species
involved in the first reaction step. Thus, the simultaneous
presence of supplementary nucleophilic site can divert from
the expected 4þ1 cyclo-condensation. Anyway, suitable
hetero-aromatic amines could be employed at this
purpose.12a,b
Analytical and spectroscopic data for compounds 1a,b were
consistent to those previously reported.13,14 The yield of
compound 1b was optimized to 92% with respect to the
reported 50%13 by using the following modified procedure.
To a solution of sodium ethoxide (80 mmol) in absolute
ethanol (100 ml), acetylacetone (80 mmol) was added
dropwise cooling with an ice-bath. After 1 h, the mixture
was allowed to rt and the 2-nitrophenacyl bromide was
added in small portions within 40 min. The reaction mixture
was stirred at rt for 3 days and then quenched with 150 ml of
water. A white solid was formed and was recrystallized
from ethanol.
3. Conclusions
In summary, the above presented study allows easy access
to fully aromatic pyrrolo[3,2-c]quinoline derivatives. This
new approach is operationally simple and makes use of
commercial available starting materials such as alkyl, aryl
or heteroaryl amines concerned in step (i) and aryl or
heteroaryl aldehydes25 involved in step (iii). In contrast to
previous methods, this new pathway allows convenient
4.2. General method for the preparation of 5-(o-nitro-
phenyl)-1,3-substituted pyrroles (2a–e)
According to the procedure described13 for 2a–e, to a

M. L. Testa et al. / Tetrahedron 60 (2004) 5873–5880
5877
solution of 1a,b (10 mmol) in acetic acid (40 ml), the
corresponding amine (10 mmol) was added. The mixture
was heated under reflux for 3–8 h until disappearance of
reactants (TLC monitorage). After cooling, the resultant
solution was poured onto crushed ice. The so formed
solid was filtered off, air-dried and recrystallized from
ethanol.
129.16 (d, NPh C-3,5), 128.45 (d, NPhC-4), 128.02 (d, NPh
C-2,6), 128.02 (s, C-5), 126.23 (s, C-10), 123.84 (d, C-30),
121.29 (s, C-3), 111.07 (d, C-4), 28.53 (q, COMe), 12.55 (q,
2-Me); m/z (EI) 320 (59, Mþ), 305 (15), 261 (49), 228 (72),
186 (44), 118 (91), 77 (100), 51 (42), 43 (78%).
4.3. General method for the preparation of 5-(2-amino-
phenyl)-1-substituted-pyrroles (3a–e)
Analytical and spectroscopic data for compounds 2a–c,e
were coincident to those previously reported.13,14,20,21 Most
detailed 1H and 13C NMR data, together with MS data, not
previously reported, are now described.
According to the procedure described19 for 2a–c,e com-
pound 2d was reduced overnight with hydrogen (50 psi)
over 10% Pd–C in ethanol in a Parr apparatus at room
temperature. The catalyst was filtered off and the solvent
evaporated under reduced pressure. The obtained solid was
recrystallized from ethanol.
4.2.1. 3-Acetyl-2-methyl-5-(2-nitrophenyl)-1H-pyrrole
2b. Yield 80%; white crystals, mp 206–207 8C [lit.13 mp
208 8C]; dH 11.75 (1H, s, exchangeable with D2O, NH),
7.92 (1H, d, J 7.5 Hz, H-30), 7.74–7.64 (2H, m, H-50 and
-60), 7.51 (1H, t, J¼7.5 Hz, H-40), 6.60 (1H, s, H-4), 2.49
(3H, s, 2-Me), 2.32 (3H, s, COMe); dC 193.28 (s, CO),
147.52 (s, C-20), 136.56 (s, C-2), 132.500(d, C-50), 130.32 (d,
C-60), 127.94 (d, C-40), 125.62 (s, C-1 ), 124.03 (d, C-30),
123.80 (s, C-5), 121.76 (s, C-3), 110.33 (d, C-4), 28.30 (q,
COMe), 13.41 (q, 2-Me); m/z (EI) 244 (100, Mþ), 229 (43),
183 (55), 77 (39), 43 (70%).
Analytical and spectroscopic data for compounds 3a–c,e
were coincident to those previously reported.13,14,20,21 Most
detailed 1H and 13C NMR data, together with MS data, not
previously reported, are now described.
4.3.1. 5-(2-Aminophenyl)-3-ethylester-2-methyl-1-phe-
nyl-1H-pyrrole 3a. Yield 95%; orange crystals, mp 154–
155 8C [lit.21 mp 153 8C]; dH 7.35–7.30 (3H, m, NPh H-3,5
and -4), 7.24 (2H, dd, J¼7.8, 2.2 Hz, NPh H-2,6), 6.86 (1H,
ddd, J¼8.0, 7.6, 1.3 Hz, H-40), 6.69 (1H, dd, J¼7.6, 1.3 Hz,
H-60), 6.54 (1H, dd, J¼8.0, 0.8 Hz, H-30), 6.49 (1H, s, H-4),
6.31 (1H, td, J¼7.6, 0.8 Hz, H-50), 4.81 (2H, s, exchange-
able with D2O, NH2), 4.22 (2H, q, J¼7.1 Hz, CH2Me), 2.30
(3H, s, 2-Me), 1.28 (3H, t, J¼7.1 Hz, CH2Me); dC 164.56 (s,
CO), 147.14 (s, C-20), 137.26 (s, NPh C-1), 136.36 (s, C-2),
131.50 (d, C-60), 130.52 (s, C-5), 128.71 (d, NPh C-3,5),
128.61 (d, C-40), 128.005 (d, NPh C-2,60and -4), 116.04 (s,
C-10), 115.26 (d, C-5 ), 114.29 (d, C-3 ), 111.61 (s, C-3),
109.52 (d, C-4), 58.82 (t, CH2Me), 14.45 (q, CH2Me), 12.35
(q, 2-Me); m/z (EI) 320 (100, Mþ), 275 (31), 274 (44), 130
(44), 118 (57), 77 (33), 51 (12%).
4.2.2. 3-Acetyl-1,2-dimethyl-5-(2-nitrophenyl)-1H-
pyrrole 2c. Yield 87%; orange crystals, mp 115–116 8C
[lit.20 mp 116–117 8C]; dH 8.07 (1H, d, J¼8.1 Hz, H-30),
7.79 (1H, t, J¼7.4 Hz, H-50), 7.69 (1H, dd, J¼8.1, 7.4 Hz,
H-40), 7.57 (1H, d, J¼7.4 Hz, H-60), 6.52 (1H, s, H-4), 3.27
(3H, s, NMe), 2.52 (3H, s, 2-Me), 2.28 (3H, s, COMe); dC
193.36 (s, CO), 149.45 (s, C-20), 135.970(s, C-2), 133.46 (d,
C-60), 133.01 0(d, C-50), 129.85 (d, C-4 ), 127.02 (s, C-5),
126.05 (s, C-1 ), 124.08 (d, C-30), 120.34 (s, C-3), 110.26 (d,
C-4), 31.06 (q, NMe), 28.23 (q, COMe), 11.41 (q, 2-Me);
m/z (EI) 258 (96, Mþ), 243 (80), 196 (81), 77 (64), 56 (100),
43 (86%).
4.2.3. 3-Acetyl-1-ethyl-2-methyl-5-(2-nitrophenyl)-1H-
pyrrole 2d. Yield 60%; white crystals, mp 133–134 8C;
[found: C, 66.29; H, 5.94; N, 10.27. C15H16N2O3 requires C,
66.16; H, 5.92; N, 10.29%]; nmax 1643 (CO), 1527 and 1348
(NO2) cm21; dH 8.05 (1H, d, J¼7.8 Hz, H-30), 7.78 (1H, t,
J¼7.2 Hz, H-50), 7.69 (1H, dd, J¼7.8, 7.2 Hz, H-40), 7.60
(1H, d, J¼7.2 Hz, H-60), 6.46 (1H, s, H-4), 3.77 (2H, q,
J¼7.1 Hz, CH2Me), 2.55 (3H, s, 2-Me), 2.26 (3H, s, COMe),
1.04 (3H, t, J¼7.1 Hz, CH2Me); dC 193.37 (s, CO), 149.93
(s, C-20), 135.02 (s, C-2), 133.48 (d, C-60), 132.68 (d, C-50),
129.99 (d, C-40), 126.02 (s, C-10), 125.92 (s, C-5), 123.91 (d,
C-30), 120.60 (s, C-3), 110.55 (d, C-4), 38.64 (t, CH2Me),
28.21 (q, COMe), 15.09 (q, CH2Me), 11.28 (q, 2-Me); m/z
(EI) 272 (100, Mþ), 257 (33), 210 (25), 77 (21), 70 (71), 43
(70), 42 (91%).
4.3.2. 3-Acetyl-5-(2-aminophenyl)-2-methyl-1H-pyrrole
3b. Yield 97%; white crystals, mp 130–131 8C [lit.13
mp132 8C]; dH 11.39 (1H, s, exchangeable with D2O, NH),
7.20 (1H, dd, J¼7.5, 1.3 Hz, H-60), 7.00 (1H, ddd, 0J¼7.9,
7.5, 1.3 Hz, H-40), 6.78 (1H, dd, J¼7.9, 1.0 Hz, H-3 ), 6.69
(1H, s, H-4), 6.63 (1H, td, J¼7.5, 1.0 Hz, H-50), 5.02 (2H, s,
exchangeable with D2O, NH2), 2.49 (3H, s, 2-Me), 2.34 (3H,
s, COMe); dC 193.61 (s, CO), 144.90 (s, C-20), 134.77 (s,
C-2), 127.92 (d, C-60), 127.49 (d, C-40), 127.12 (s, C-5),
121.14 (s, C-3), 116.94 (s, C-10), 116.50 (d, C-50), 115.56 (d,
C-30), 108.52 (d, C-4), 28.40 (q, COMe), 13.35 (q, 2-Me);
m/z (EI) 214 (100, Mþ), 199 (85), 172 (69), 171 (73), 100
(82), 77 (31), 43 (32%).
4.3.3. 3-Acetyl-5-(2-aminophenyl)-1,2-dimethyl-1H-pyr-
role 3c. Yield 91%; white crystals, mp 134–135 8C [lit.021
mp 135 8C]; dH 7.09 (1H, ddd, J¼8.0, 7.3, 1.1 Hz, H-4 ),
6.95 (1H, dd, J¼7.3, 1.1 Hz, H-600), 6.76 (1H, d, J¼8.0 Hz,
H-30), 6.59 (1H, t, J¼7.3 Hz, H-5 ), 6.44 (1H, s, H-4), 4.81
(2H, exchangeable with D2O, NH2), 3.26 (3H, s, NMe), 2.51
(3H, s, 2-Me), 2.30 (3H, s, COMe); dC 193.45 (s, CO),
147.19 (s, C-20), 135.19 (s, C-2), 131.46 (d, C-60), 130.00 (s,
C-5), 129.15 (d, C-40), 120.120 (s, C-3), 116.17 (s, C-10),
115.83 (d, C-50), 114.55 (d, C-3 ), 109.49 (d, C-4), 30.63 (q,
NMe), 28.28 (q, COMe), 11.63 (q, 2-Me); m/z (EI) 228 (90,
4.2.4. 3-Acetyl-2-methyl-5-(2-nitrophenyl)-1-phenyl-1H-
pyrrole 2e. Yield 80%; yellow crystals, mp 137–138 8C
[lit.20 mp 138 8C]; dH 7.82 (1H, d, J¼8.0 Hz, H-30), 7.61
(1H, t, J¼7.3 Hz, H-50), 7.49 (1H, dd, J¼8.0, 7.3 Hz, H-40),
7.45 (1H, d, J¼7.3 Hz, H-60), 7.39–7.33 (3H, m, NPh H-3,5
and -4), 7.14 (2H, dd, J¼7.9, 1.6 Hz, NPh H-2,6), 6.79 (1H,
s, H-4), 2.39 (3H, s, COMe), 2.33 (3H, s, 2-Me); dC 193.81
(s, CO), 148.72 (s, C-20), 136.35 (s, C-2),135.84 (s, NPh
C-1), 133.43 (d, C-60), 132.71 (d, C-50), 129.30 (d, C-40),

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M. L. Testa et al. / Tetrahedron 60 (2004) 5873–5880
Mþ), 213 (100), 185 (52), 106 (64), 77 (23), 56 (51), 43
(26%).
H-3,5 and -4), 7.22 (1H, ddd, J¼8.1, 7.4, 1.3 Hz, H-8), 6.88
(1H, dd, J¼8.1, 1.1 Hz, H-9), 3.58 (2H, q, J¼7.2 Hz,
CH2Me), 2.31 (3H, s, 2-Me), 0.74 (3H, t, J¼7.2 Hz,
CH2Me); dC 163.01 (s, CO), 151.86 (s, C-4), 144.07 (s,
C-5a), 141.89 (s, Ph C-1), 137.88 (s, C-2 and NPh C-1),
135.33 (s, C-9b), 130.66 (d, NPh C-3,5), 130.45 (d, NPh
C-4), 129.97 (d, C-6), 128.75 (d, NPh C-2,6), 128.29 (d, Ph
C-4), 128.05 (d, Ph C-2,6 and -3,5), 126.95 (d, C-7), 125.58
(d, C-8), 119.91 (d, C-9), 116.70 (s, C-3a), 115.97 (s, C-9a),
115.62 (s, C-3), 60.00 (t, CH2Me), 13.33 (q, CH2Me), 11.65
(q, 2-Me); m/z (EI) 406 (92, Mþ), 377 (100), 361 (61), 333
(46), 255 (13), 180 (19), 165 (34), 77 (20%).
4.3.4. 3-Acetyl-5-(2-aminophenyl)-1-ethyl-2-methyl-1H-
pyrrole 3d. Yield 82%; yellow crystals, mp 88–89 8C;
[found: C, 74.25; H, 7.51; N, 11.58. C15H18N2O requires C,
74.35; H, 7.49; N, 11.56%]; nmax 3464 (NH2), 3366 (NH2),
1643 (CO) cm21; dH 7.10 (1H, ddd, J¼7.9, 7.5, 1.3 Hz,
H-40), 6.97 (1H, dd, J¼7.5, 1.3 Hz, H-60), 6.75 (1H, d,
J¼7.9 Hz, H-30), 6.60 (1H, t, J¼7.5 Hz, H-50), 6.42 (1H, s,
H-4), 4.73 (2H, exchangeable with D2O, NH2), 3.70 (2H, q,
J¼7.1 Hz, CH2Me), 2.53 (3H, s, COMe), 2.30 (3H, s, 2-Me),
0.98 (3H, t, J¼7.1 Hz, CH2Me); dC 193.71 (s, CO), 147.26
(s, C-20), 134.44 (s, C-2), 131.64 (d, C-60), 129.39 (d, C-40),
129.04 (s, C-5), 120.50 (s, C-3), 116.39 (s, C-10), 115.99 (d,
C-50), 114.58 (d, C-30), 110.16 (d, C-4), 38.29 (t, CH2Me),
28.41 (q, COMe), 15.57 (q, CH2Me), 11.52 (q, 2-Me); m/z
(EI) 242 (100, Mþ), 227 (98), 199 (43), 99 (33), 77 (18), 43
(32%).
4.4.2. 3-Acetyl-2-methyl-4-phenyl-1H-pyrrolo[3,2-
c]quinoline 4b. Yield 85%; yellow crystals, mp 157–
158 8C; [found: C, 80.15; H, 5.39; N, 9.30. C20H16N2O
requires C, 79.98; H, 5.37; N, 9.33%]; nmax 3225 (NH),
1647 (CO) cm21; dH 12.89 (1H, s, exchangeable with D2O,
NH), 8.39 (1H, dd, J¼7.6, 1.5 Hz, H-9), 8.06 (1H, dd,
J¼8.0,1.3 Hz, H-6), 7.70–7.60 (4H, m, H-7, H-8, and Ph
H-2,6), 7.51–7.48 (3H, m, Ph H-3,5 and -4), 2.55 (3H, s,
2-Me), 1.58 (3H, s, COMe); dC 196.85 (s, CO), 153.66 (s,
C-4), 143.25 (s, C-5a), 142.08 (s, Ph C-1), 138.98 (s, C-2),
135.26 (s, C-9b), 129.25 (d, C-6), 128.75 (d, Ph C-4),
128.59 (d, Ph C-3,5), 128.42 (d, Ph C-2,6), 127.22 (d, C-7),
125.99 (d, C-8), 120.84 (d, C-9), 117.74 (s, C-3), 116.14 (s,
C-3a), 116.08 (s, C-9a), 31.24 (q, COMe), 12.83 (q, 2-Me);
m/z (EI) 300 (64, Mþ), 285 (75), 255 (27), 128 (100), 114
(30%).
4.3.5. 3-Acetyl-5-(2-aminophenyl)-2-methyl-1-phenyl-
1H-pyrrole 3e. Yield 85%; yellow crystals, mp 151–
152 8C [lit.21 mp 153 8C]; dH 7.40–7.32 (3H, m, NPh H-3,5
and -4), 7.24 (2H, dd, J¼7.5, 1.9 Hz, NPh H-2,6), 6.88 (1H,
ddd, J¼8.0, 7.3, 1.3 Hz, H-40), 6.71 (1H, dd, J¼7.3, 1.3 Hz,
H-60), 6.70 (1H, s, H-4), 6.59 (1H, dd, J¼8.0, 1.0 Hz, H-30),
6.33 (1H, td, J¼7.3, 1.0 Hz, H-50), 4.93 (2H, s, exchange-
able with D2O, NH2), 2.41 (3H, s, COMe), 2.32 (3H, s,
2-Me); dC 193.97 (s, CO), 147.03 (s, C-20), 137.02 (s, NPh
C-1), 135.36 (s, C-2), 131.53 (d, C-60), 130.18 (s, C-5),
128.70 (d, NPh C-3,5), 128.60 (d, C-40), 128.02 (d, NPh
C-4), 127.98 (d, NPh C-2,6), 120.77 (s, C-3), 116.13 (s,
C-10), 115.33 (d, C-50), 114.36 (d, C-30), 110.52 (d, C-4),
28.56 (q, COMe), 12.74 (q, 2-Me); m/z (EI) 290 (100, Mþ),
275 (98), 247 (40), 130 (61), 118 (42), 77 (83), 51 (49%).
4.4.3. 3-Acetyl-1,2-dimethyl-4-phenyl-1H-pyrrolo[3,2-
c]quinoline 4c. Yield 77%; yellow crystals, mp 184–
185 8C; [found: C, 80.31; H, 5.75; N, 8.93. C21H18N2O
requires C, 80.23; H, 5.77; N, 8.91%]; nmax 1651
(CO) cm21; dH 8.56 (1H, dd, J¼8.0, 1.1 Hz, H-9), 8.11
(1H, dd, J¼7.8, 1.1 Hz, H-6), 7.70–7.55 (4H, m, J H-7, H-8
and Ph H-2,6), 7.51–7.47 (3H, m, Ph H-3,5 and -4), 4.13
(3H, s, NMe), 2.47 (3H, s, 2-Me), 1.51 (3H, s, COMe); dC
197.76 (s, CO), 153.22 (s, C-4), 144.02 (s, C-5a), 141.73 (s,
Ph C-1), 139.26 (s, C-2), 134.70 (s, C-9b), 129.66 (d, C-6),
128.76 (d, Ph C-4), 128.54 (d, Ph C-3,5), 128.40 (d, Ph
C-2,6), 126.59 (d, C-7), 125.73 (d, C-8), 121.25 (d, C-9),
117.51 (s, C-3), 116.71 (s, C-9a), 115.70 (s, C-3a), 34.15
(q, NMe), 31.46 (q, COMe), 10.94 (q, 2-Me); m/z (EI) 314
(89, Mþ), 299 (100), 283 (47), 255 (53), 127 (65), 114
(31%).
4.4. General method for the preparation of 1,3,4-
substituted-pyrrolo[3,2-c]quinoline derivatives (4a–f)
To a solution of aminopyrroles 3a–e (0.57 mmol), in DMF
(5 ml) commercial aldehydes (0.63 mmol) and catalytic
amount of p-TsOH (15 mol%) were added. After stirring at
100 8C for 1–3 h, (TLC monitorage) the mixture was
allowed to reach room temperature. Evaporation of the
solvent under reduced pressure gave rise a dark residue
which was dissolved in dichloromethane (30 ml) and
washed with 3£10 ml of 5% aqueous NaHCO3 solution.
The organic extracts dried with MgSO4 and evaporated in
vacuo afforded a solid which was purified by column
chromatography (eluant dichloromethane/ethyl acetate, 9:1,
followed by recrystallization from ethanol).
4.4.4. 3-Acetyl-1-ethyl-2-methyl-4-phenyl-1H-pyr-
rolo[3,2-c]quinoline 4d. Yield 84%; yellow crystals, mp
197–198 8C; [found: C, 80.37; H, 6.16; N, 8.50. C22H20N2O
requires C, 80.46; H, 6.14; N, 8.53%]; nmax 1667
(CO) cm21; dH 8.50 (1H, dd, J¼8.0, 1.2 Hz, H-9), 8.17
(1H, dd, J¼8.1, 1.1 Hz, H-6), 7.75–7.65 (4H, m, H-7, H-8,
and Ph H-2,6), 7.55–7.51 (3H, m, Ph H-3,5 and -4), 4.69
(2H, q, J¼7.2 Hz, CH2Me), 2.54 (3H, s, 2-Me), 1.52 (3H, s,
COMe), 1.50 (3H, t, J¼7.2 Hz, CH2Me); dC 197.83 (s, CO),
152.95 (s, C-4), 142.80 (s, C-5a), 140.47 (s, Ph C-1), 139.20
(s, C-2), 133.94 (s, C-9b), 129.20 (d, C-6), 128.88 (d, Ph
C-4), 128.63 (d, Ph C-2,6), 128.58 (d, Ph C-3,5), 126.63 (d,
C-7), 125.46 (d, C-8), 121.10 (d, C-9), 118.12 (s, C-3),
116.05 (s, C-3a and C-9a), 40.61 (t, CH2Me), 31.46 (q,
COMe), 14.70 (q, CH2Me), 10.52 (q, 2-Me); m/z (EI) 328
(88, Mþ), 313 (100), 285 (56), 255 (41), 128 (19%).
In the case of aminopyrrole 3b, along with the compound 4b
obtained in 85% of yield, compound 5 was isolated in 2% of
yield.
4.4.1. 3-Ethylester-2-methyl-1,4-diphenyl-1H-pyr-
rolo[3,2-c]quinoline 4a. Yield 84%; white crystals, mp
273–274 8C; [found: C, 79.62; H, 5.48; N, 6.87.
C27H22N2O2 requires C, 79.78; H, 5.46; N, 6.89%]; nmax
1709 (CO) cm21; dH 8.08 (1H, dd, J¼8.0, 1.3 Hz, H-6),
7.78–7.74 (3H, m, NPh H-3,5 and -4), 7.71–7.61 (4H, m,
NPh H-2,6 and Ph H-2,6), 7.58–7.46 (4H, m, H-7 and Ph

M. L. Testa et al. / Tetrahedron 60 (2004) 5873–5880
5879
4.4.5. 3-Acetyl-2-methyl-1,4-diphenyl-1H-pyrrolo[3,2-
c]quinoline 4e. Yield 94%; yellow crystals, mp 259–
260 8C; [found: C, 83.15; H, 5.37; N, 7.45. C26H20N2O
requires C, 82.95; H, 5.35; N, 7.44%];. nmax 1664
(CO) cm21; dH 8.10 (1H, dd, J¼8.0, 1.1 Hz, H-6), 7.78–
7.72 (5H, m, Ph H-2,6 and NPh H-3,5 and -4), 7.63 (2H, dd,
J¼7.2, 1.9 Hz, NPh H-2,6), 7.57–7.53 (4H, m, H-7 and Ph
H-3,5 and -4), 7.24 (1H, ddd, J¼8.0, 7.4, 1.1 Hz, H-8), 6.90
(1H, dd, J¼8.0, 1.3 Hz, H-9), 2.20 (3H, s, 2-Me), 1.64 (3H,
s, COMe); dC 197.72 (s, CO), 153.43 (s, C-4), 143.81 (s,
C-5a), 141.32 (s, PhC-1), 139.64 (s, C-2), 137.76 (s, NPh
C-1), 135.17 (s, C-9b), 130.59 (d, NPh C-3,5), 130.33 (d,
NPh C-4), 129.51 (d, C-6), 128.95 (d, PhC-4), 128.65 (d,
NPh C-2,6 and PhC-3,5), 128.47 (d, PhC-2,6), 127.06 (d,
C-7), 125.65 (d, C-8), 120.00 (d, C-9), 118.20 (s, C-3),
115.98 (s, C-9a), 115.90 (s, C-3a), 31.43 (q, COMe), 11.55
(q, 2-Me); m/z (EI) 376 (49, Mþ), 361 (100), 255 (8), 180
(16), 165 (17), 77 (11%).
zolo[1,5-a]pyrimidin-6-yl)-1-ethanone 6 was isolated (yield
60%) and crystallized from ethanol as white crystals, mp
149–150 8C; [found: C, 62.84; H, 4.99; N, 17.18.
C17H16N4O3 requires C, 62.95; H, 4.97; N, 17.27%]; nmax
1705 (CO), 1545 and 1350 (NO2) cm21; dH 8.17 (1H, d,
J¼8.0 Hz, H-300), 8.00 (1H, d, J¼7.4 Hz, H-60), 7.940 (1H, t,
J¼7.4 Hz, H-5 ), 7.82 (1H, dd, J¼8.0, 7.4 Hz, H-4 ), 6.36
(1H, s, H-3), 4.57 (2H, s, CH2), 2.67 (3H, s, 7-Me), 2.48 (3H,
s, 5-Me), 2.41 (3H, s, 2-Me); dC 198.51 (s, CO), 157.94 (s,
C-5), 153.13 (s, C-2), 147.30 (s, C-3a), 145.92 (s, C-20),
143.94 (s, C-7), 135.41 (s, C-10), 134.25 (d, C-50), 131.91 (d,
C-40), 128.27 (d, C-60), 124.47 (d, C-30), 110.67 (s, C-6),
94.30 (d, C-3), 41.22 (t, CH2), 23.23 (q, 5-Me), 14.30 (q,
2-Me), 13.41 (q, 7-Me); m/z (EI) 324 (30, Mþ), 174 (100),
81 (53), 53 (34%).
Reduction of 6 under the conditions specified in Section 4.3
gave the 1-(2-amino-phenyl)-2-(2,5,7-trimethyl-pyra-
zolo[1,5-a]pyrimidin-6-yl)-1-ethanone 8: yield 85%; white
crystals, mp 177–178 8C; [found: C, 69.40; H, 6.18; N,
18.99. C17H18N4O requires C, 69.37; H, 6.16; N, 19.03%];
4.4.6. 3-Acetyl-2-methyl-4-(5-methylfuran-2yl)-1-phe-
nyl-1H-pyrrolo[3,2-c]quinoline 4f. Yield 72%; yellow
crystals, mp 252–253 8C; [found: C, 78.69; H, 5.28; N,
7.38. C25H20N2O2 requires C, 78.93;H, 5.30; N, 7.36%];
nmax 1672 (CO) cm21; dH 8.02 (1H, dd, J¼8.1, 1.1 Hz,
H-6), 7.76–7.73 (3H, m, NPh H-3,5 and -4), 7.63 (2H, dd,
J¼7.1, 2.3 Hz, NPh H-2,6), 7.53 (1H, ddd, J¼8.1, 7.0,
1.3 Hz, H-7), 7.19 (1H, ddd, J¼8.2, 7.0, 1.1 Hz, H-8), 7.13
(1H, d, J¼3.5 Hz, Furanyl H-3), 6.84 (1H, dd, J¼8.2,
1.3 Hz, H-9), 6.38 (1H, d, J¼3.5 Hz, Furanyl H-4), 2.34
(3H, s, Furanyl-Me), 2.20 (3H, s, 2-Me), 2.01 (3H, s,
COMe); dC 197.60 (s, CO), 153.09 (s, Furanyl C-5), 152.16
(s, C-4), 143.92 (s, C-5a), 143.16 (s, Furanyl C-2), 138.73
(s, C-2), 137.81 (s, NPh C-1), 135.13 (s, C-9b), 130.52 (d,
NPh C-3,5), 130.25 (d, NPh C-4), 129.45 (d, C-6), 128.69
(d, NPh C-2,6), 126.98 (d, C-7), 125.28 (d, C-8), 119.93 (d,
C-9), 117.99 (s, C-3), 116.09 (s, C-9a), 114.20 (s, C-3a),
111.30 (d, Furanyl C-3), 108.71 (d, Furanyl C-4), 31.34 (q,
COMe), 13.26 (q, Furanyl-Me), 11.33 (q, 2-Me); m/z (EI)
380 (98, Mþ), 365 (82), 337 (100), 293 (33), 77 (21), 43
(18%).
n
max 3437 and 3350 (NH2), 1616 (CO) cm21; dH 8.06 (1H,
d, J¼7.4 Hz, H-60), 7.30 (1H, dd, J¼8.2, 7.4 Hz, H-40), 7.16
(2H, s, exchangeable with D2O, NH2), 6.80 (1H, d,
J¼8.2 Hz, H-30), 6.63 (1H, t, J¼7.4 Hz, H-50), 6.33 (1H,
s, H-3), 4.52 (2H, s, CH2), 2.58 (3H, s, 7-Me), 2.41 (3H, s,
2-Me), 2.34 (3H, s, 5-Me); dC 197.91 (s, CO), 158.04 (s,
C-5), 152.68 (s, C-2), 151.26 (s, C-20), 147.24 (s, C-3a),
143.36 (s, C-7), 134.45 (d, C-40), 131.33 0(d, C-60), 117.02 (d,
C-30), 116.15 (s, C-10), 114.47 (d, C-5 ), 113.07 (s, C-6),
94.06 (d, C-3), 37.81 (t, CH2), 23.26 (q, 5-Me), 14.30 (q,
2-Me), 13.38 (q, 7-Me); m/z (EI) 294 (33, Mþ), 201 (19),
174 (33), 120 (100), 92 (30), 65 (29).
Acknowledgements
We would like to express our gratitude to R. Scalici and
G. Ruggieri for technical support as well as CNR and MIUR
for financial support. We thank sincerely Professor A. M.
Almerico and G. Poli for fruitful discussions.
4.4.7. 2-Acetyl-3-methyl-5-phenyl-5,6-dihydro-pyr-
rolo[1,2-c]quinazoline 5. Yield 2%; yellow crystals, mp
195–196 8C; [found: C, 79.41; H, 5.97; N, 9.18. C20H18N2O
requires C, 79.44; H, 6.00; N, 9.26%]; nmax 3342 (NH),
1641 (CO) cm21; dH 7.52 (1H, d, J¼7.4 Hz, H-10), 7.33
(1H, s, exchangeable with D2O, NH), 7.27–7.23 (3H, m,
H-30,50 and -40), 7.06 (1H, s, H-1), 6.98 (1H, d0d, 0J¼7.8,
7.4 Hz, H-8), 6.92 (2H, dd, J¼7.5, 1.1 Hz, H-2 ,6 ), 6.75
(1H, t, J¼7.4 Hz, H-9), 6.72 (1H, d, J¼7.8 Hz, H-7), 6.62
(1H, s, H-5), 2.43 (3H, s, 3-Me), 2.40 (3H, s, COMe); dC
194.06 (s, CO), 141.29 0(s, C-6a), 138.32 (s, C-10), 132.28 (s,
C-3), 128.54 (d, C-30,5 ), 128.01 (d, C-8), 127.23 (d, C-40),
126.23 (s, C-10b), 125.21 (d, C-20,60), 121.88 (d, C-10),
121.59 (s, C-2), 118.55 (d, C-9), 115.95 (s, C-10a), 115.11
(d, C-7), 103.81 (d, C-1), 65.51 (d, C-5), 28.58 (q, COMe),
10.85 (q, 3-Me); m/z (EI) 302 (94, Mþ), 287 (17), 259 (20),
225 (100), 77 (10), 43 (15%).
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