Reactivity of 5-(3-azidophenyl)-1-(1H-pyrrol-3-yl)pyrroles in TFMSA. A route for new ring systems as DNA-interactive agents

Article abstract of DOI:10.1016/S0040-4020(01)01033-X

Acid catalyzed decomposition of 5-(3-azidophenyl)-1-(1H-pyrrol-3-yl)pyrroles did not afford the expected dipyrrolo[2,1-a:3,4-c]isoquinoline derivatives, but the planar dipyrrolo[2,1-a:3,2-c]isoquinoline derivatives and related non planar derivatives 11bH-

Full text of DOI:10.1016/S0040-4020(01)01033-X

TETRAHEDRON
Pergamon
Tetrahedron 57 %2001) 10147±10153
Reactivity of 5-ꢀ3-azidophenyl)-1-ꢀ1H-pyrrol-3-yl)pyrroles in
TFMSA. A route for newring systems as DNA-interactive agents
Francesco Mingoiap
Istituto di Chimica e Tecnologia dei Prodotti NaturaliÐCNR, Via Ugo La Malfa 153, 90146 Palermo, Italy
Received 30 July 2001; revised 6 September 2001; accepted 27 September 2001
AbstractÐAcid catalyzed decomposition of 5-%3-azidophenyl)-1-%1H-pyrrol-3-yl)pyrroles did not afford the expected dipyrrolo[2,1-a:3,4-
c]-isoquinoline derivatives, but the planar dipyrrolo[2,1-a:3,2-c]isoquinoline derivatives and related non planar derivatives 11bH-dipyr-
rolo[2,1-a:3,2-c]isoquinoline derivatives. In strong acid media %tri¯uoromethanesulfonic acid) the a-%1-pyrrol-3yl) position even if blocked,
was more prone to undergo cyclization with respect to the free b one. Despite the steric hindrance, these compounds were obtained in
moderate to good overall yields, depending on the nature and position of the substituents on the 1-%1H-pyrrolyl) moiety. q 2001 Elsevier
Science Ltd. All rights reserved.
Among DNA-interactive agents, involving intercalation as
binding mode, the planar geometry of the molecule repre-
sents one of the most important structural features required
for the adequate insertion between the stacked base paired
oligonucleotides.1 Such compounds are of interest both
for the development of new therapeutics and in targeting
of an ongoing effort aimed to develop new polycyclic
molecules, by using 1-heteroaryl-pyrroles as key inter-
mediates and to explore their biological properties, interest
was focussed in the synthesis of the new ring system
dipyrrolo[2,1-a:3,4-c]isoquinoline as structural analog of
the bioactive pyrrolo[1,2-f ]-phenanthridines %PPH),8 and
as bioisostere of the benzo-fused isoquinoline derivative
%BFI), that showed intercalating ability with speci®c DNA
sequences9 %Fig. 1).
2
speci®c DNAsequences. To better clarify the structural
features that contribute to the DNAbinding, an approach
may involve modi®cations and functionalizations of the
ligand which in turn may lead from subtle to substantial
changes in the binding mode, location and af®nity towards
DNA.3 Moreover, the proposal of the phenanthridine moiety
as an effective pharmacophore in the classes of DNA-inter-
active compounds4 and the current clinical success of
natural fagaridine, a phenanthro-fused alkaloid,5 has
increased the attention on the synthesis6 and on the bio-
logical evaluation of related compounds.7 As an extension
Previously, some synthetic aspects regarding the utility,
scope and limitations of the preparation of substituted
PPH,10,11 and more recently of the dipyrrolo[1,2-a:10,20-c]-
quinazoline %DPQ)12 were described. In all these cases,
the synthetic pathway involved arylnitrenium ions of type
%1)±%3) as key intermediates. Such a synthetic strategy
provides the opportunity to introduce into the different
Figure 1.
Keywords: azides; arylnitrenium ions; cyclization; nitrogen heterocycles; pyrroles.
Tel.: 139-091-680-9368; fax: 139-091-680-9399; e-mail: mingoia@ictpn.pa.cnr.it
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020%01)01033-X

10148
F. Mingoia / Tetrahedron 57 ,2001) 10147±10153
Figure 2.
moieties of the molecule an amino group or other groups in
crucial positions for better DNA-intercalation4 by suitable
choice of the starting material %Fig. 2).
In order to investigate the reactivity of the pyrrole moiety to
be attacked either as a function of its position of insertion in
the entire molecule or on the nature and the position of
functional groups, the behavior of intermediates of type
%4) towards cyclization was explored, choosing at ®rst
derivatives with a simply unsubstituted b0 position.
Since the arylnitrenium ion behaves as a p-carbocation,
a suf®ciently high electron density for cyclization was
required under the reaction conditions. Thus, for inter-
mediates of type %1) cyclization took place only in the
presence of an activating methoxy group in a suitable
position on the N-linked ring. Instead, using the inter-
mediate of type %2), the same electronic effects exerted by
the pyrrole nitrogen enhanced the electrophilic character of
the p-carbocation allowing cyclization even in the absence
of a methoxy group. Upon replacement of the activated
1-phenyl substituent of %1) with an electron rich ®ve
membered heterocycle, as in intermediate of type %3), the
cyclization reaction proceeded successfully as expected
yielding %DPQ) derivatives even in the presence of an
electron withdrawing cyano group. Taking these results
into account, it was to be expected that intermediate such
as %4) containing the isomeric pyrrole moiety should also
exhibit favorable electronic requirements for cyclization.
The synthetic route is outlined in Scheme 1. The substituted
ethyl 1-%pyrrol-3-yl)-5-%3-nitrophenyl)pyrrole-3-carboxyl-
ates %7a±c) were prepared by reacting 1,4-diketone11 %6)
with substituted 3-aminopyrroles13,14 %5a±c) in re¯uxing
acetic acid. After 3±72 h, depending on basicity of
the amine, the nitro derivatives %7a±c) were obtained in
moderate to good yield %40±94%). Catalytic reduction of
the nitro group, at room temperature over palladium on
charcoal, gave the amino compounds %8a±c). Diazotization
at 0±58C with sodium nitrite in acid solution followed by
addition of an excess of sodium azide provided the azido
derivatives %9a±c) in moderate to good yields %50±85%).
The spectroscopic data obtained from the IR spectra, 1H and
13C NMR spectra, and GC±MS furnished all the expected
Scheme 1. %a) RˆH, R1ˆCOOEt; %b) RˆMe, R1ˆPh; %c) RˆR1ˆPh.

F. Mingoia / Tetrahedron 57 ,2001) 10147±10153
10149
Scheme 2. %a) RˆH, R1ˆCOOEt; %b) RˆMe, R1ˆPh; %c) RˆR1ˆPh.
signals for the structural characterization of all these
derivatives. The pyrrole NH was detected for all derivatives.
In particular, the IR spectra showed a broad peak in the
range 3200±3600 cm21 and in addition to all the other
expected signals, the 1H NMR spectrum, exhibited a signal
at dH 11.12±12.29 ppm, exchangeable with D2O. These
data are in agreement with a 1H-pyrrole form for all
derivatives.
cyclized mono-decarboxylated structure of type %11,
RˆR1ˆH) or %12) %Scheme 2). On the basis of the multi-
plicity and the coupling constants of the protons of the
benzene portion, the 1H NMR spectrum suggested the
11-amino structure %12). In fact the more deshielded proton
H-8 appeared as a doublet coupling with H-9 %Jˆ7.1 Hz)
and the up®eld signal relative to H-10 appeared as a doublet
and coupled with the latter with Jˆ8.3 Hz. The two protons
H-2 and H-3 appeared as doublets at dH 7.2 and 6.89 ppm,
respectively, with Jˆ2.5 Hz. This J value, even if solvent
dependent, results in the typical range for the a,b coupling
rather than the a,a one. Therefore the cyclized product is a
derivative of the dipyrrolo[2,1-a:3,2-c]isoquinoline ring
system %12) and the expected dipyrrolo[2,1-a:3,4-c]iso-
quinoline %11) has to be ruled out.
Treatment of the azido derivative %9a) in dichloromethane
solution from 08C to room temperature with a two-fold
excess of tri¯uoromethanesulfonic acid %TFMSA) within
6 h, allowed the isolation of a stable compound for which
the mass spectra furnished the molecular ion at m/z 307 and
a peak of comparable intensity at m/z 278 relative to the lost
of an ethyl group. These data were compatible with a
These ®ndings could be explained supposing that the low
pH value of the medium, favored the hydrolysis and suc-
cessive decarboxylation of the R1 group %COOEt). The
resulting free a 1-pyrrol-3yl position competes with the b
one for the cyclization reaction giving rise to derivative %12)
rather than %11 RˆR1ˆH). In this way the cyclization
reaction, that occurs in a following step, on the a position
was preferred with respect to b one as it can be expected for
the electrophilic attack in pyrrole series when there is
competition between a and b positions.
Table 1. Representative 13C NMR signals %ppm) of cyclized compounds
Carbons
Compounds
12
14b
15b
14c
15c
C-11b
5-Me
CO
±OCH2±
±CH3
C-2
97.15
14.43
164.96
59.09
12.97
84.93
14.28
174.03
59.36
11.41
83.67
14.24
172.81
59.35
11.47
85.21
13.94
171.74
59.10
11.38
84.13
14.29
171.62
59.43
11.62
101.68
163.84
163.85
163.86
163.89
It has to be noticed that in the reaction conditions only the

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F. Mingoia / Tetrahedron 57 ,2001) 10147±10153
ethyl carboxylate group in the b position of the 1-pyrrolyl
moiety %NH pyrrole) easily hydrolyses and has been lost,
whereas the one in the b position of the pyrrole moiety
%N-substituted) remains unaffected.
a0 and b0 positions, reduces the overall yield of the stable
cyclized products to 60%. To our knowledge, the decom-
position of azides %9b,c) represent the ®rst examples of a
ring closure leading to a non aromatic structure instead of
the expected planar derivatives of dipyrrolo[2,1-a:3,4-
c]isoquinoline of type %11). Although, in several examples
the b pyrrolyl position has proved to be nucleophilic enough
to undergo both facile protonation15 and to undergo electro-
philic attack by a weak electrophile such as ±NvN1, as
demonstrated in the case of the synthesis of the pyrrolo-
cinnoline ring.16 In this cyclization, steric effects and
thermodynamic aspects do not seem to play a decisive
role. In fact, the ring closure occurs easily even at expense
of the loss of planarity.
As previously observed for derivatives unsubstituted at
the a,b position of the 1-pyrrolyl moiety,12 the 11-amino
derivative %12) was isolated in low yield %15%). This fact
has probably to be ascribed to the extensive decomposition
or formation of unstable by-products under the strong acid
reaction conditions.
Replacing the ethyl carboxylate group with an non-hydro-
lizable %and bulky group), such as methyl or phenyl, it was to
be expected that the free b position could be the preferable
site for cyclization leading to compounds of type %11).
Thus, azido derivatives %9b,c) were subjected to the same
experimental conditions speci®ed above.
In summary, depending on the nature and the effect of the
substituents located on the 1-pyrrol-3-yl moiety, this
method represents an ef®cient and reproducible access to
the planar 11-amino-1H-dipyrrolo[2,1-a:3,4-c]isoquinoline
%12) and non planar 9- and 11-amino-2H-dipyrrolo[2,1-a:
3,4-c]isoquinoline %14,15b,c). Under strong acidic reaction
conditions, although blocked, the a 1-pyrrolyl position
remains the favorite one to undergo electrophilic attack by
arylnitrenium ion. These results indicate that 1-pyrrol-3-yl
moiety exhibits nucleophilicity comparable with that of
1-pyrrol-2-yl isomers.12 Further investigations directed to
elucidate some mechanistic aspects are in progress.
The GC±MS analysis of the reaction mixtures revealed the
presence of pairs of isomers, with molecular ions at m/z 397
and 459, respectively, in agreement with the expected
cyclized compounds. In addition the peaks relative to the
loss of the ethyl chain %M229) and the phenyl group
%M277) were detected. However, no evidence for the
presence of the NH was found in the IR spectrum or in
1
1
the H NMR spectra. Moreover in the H NMR spectra, a
sharp singlet at dH 5.75±6.82 ppm indicated that the b
proton of the pyrrolyl moiety was still present together
with another singlet in the range dH 6.66±7.30 ppm due to
the pyrrole b proton ortho to the 3-ethyl carboxylate group.
Additionally, these cyclized derivatives showed, in the 13C
NMR spectra, a well distinguishable quaternary carbon
signal in the range dC 83.67±85.21 ppm as con®rmed in
the DEPT. This fact together with the appearance of a
carbon signal in the range dC 163.84±163.89 ppm typical
of a CvN and attributable to C-2 con®rms the presence of a
carbon with sp3 hybridization and therefore a 2H-pyrrole
like structure is proposed. In Table 1, some representative
values of 13C NMR signals are reported, that indicate the
different pattern of signals obtained for the cyclized
compounds derived from the reaction of azides %9a) and
%9b,c).
1. Experimental
All melting points were taken on a Sanyo±Gallenkamp
capillary apparatus and are uncorrected; IR spectra were
determined in bromoform with a JASCO FT/IR 5300
spectrophotometer; 1H and 13C 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 5989AGC±MS apparatus. Flash
column chromatography was performed on Kieselgel 60
%Merck) 0.040±0.063 mm.
Substituted 3-aminopyrroles %5a±c)13,14 and ethyl 1-%3-
nitrophenacyl)-1,4-pentandione-3-carboxylate %6)11 were
prepared according to literature procedure.
Thus, on the basis of the spectroscopic data, the compounds
isolated from the decomposition of the azido compounds
%9b) and %9c), were assigned as 11- and 9-amino-11bH-
dipyrrolo[2,1-a:3,2-c]isoquinolines of type %14) and %15),
respectively. In spite of the steric hindrance due to the
bulky phenyl group in the intermediate arylnitrenium ions
%10b,c), the two stable isomers can be isolated in good
yields including those %derivatives of type 14) deriving
from ortho±ortho cyclization. As evidenced from the
limited side reactions, a considerably cleaner behavior
was observed for intermediate %10b) in which the favorable
electronic effects %Ph and Me group as substituents) allowed
the isolation of the two possible isomers in high yields
%90%), together with a little amount of the hydroxyphenyl
derivative %13) and traces of the amine %8b), probably due to
the competing intermolecular nucleophilic reactions with
tri¯ate or water, or by hydrogen abstraction, respectively,
as already observed in previous reports.10,11 In the case of
intermediate %10c), the presence of two phenyl groups in the
1.1. General method for the preparation of 2,5-disub-
stituted ethyl 1-ꢀpyrrol-3-yl)-5-ꢀ3-nitrophenyl)pyrrole-3-
carboxylate ꢀ7a±c)
Asolution of ethyl 1-%3-nitrophenacyl)-1,4-pentanedione-3-
carboxylate %6) %4.4 g 15 mmol) and aminopyrrole %5a±c)
%15 mmol) in acetic acid %50 mL) was heated under re¯ux
for 3±72 h %TLC monitorage). After cooling, the resultant
brown mixture was poured onto ice-water. The solid formed
was ®ltered off, air dried, puri®ed by column chroma-
tography %eluant dichloromethane), and recrystallized
from ethanol.
1.1.1. Ethyl 1-ꢀpyrrol-3-yl)-5-ꢀ3-nitrophenyl)pyrrole-
3,20-dicarboxylate ꢀ7a). Yellow crystals, yield 40%;
MS: m/z 411 %M1) was directly reduced into the amino-
derivative %8a).

F. Mingoia / Tetrahedron 57 ,2001) 10147±10153
10151
1.1.2. Ethyl 1-ꢀ5-methyl-2-phenylpyrrol-3-yl)-5-ꢀ3-nitro-
phenyl)pyrrole-3-carboxylate ꢀ7b). Yellow±orange
crystals, yield 90%, mp 182±1848C; 3333 %NH), 1682
Calcd for C21H23N3O4: C, 66.13; H, 6.08; N, 11.02. Found:
C, 66.25; H, 6.11; N, 9.95.
%CO), 1530 and 1346 %NO2) cm21
;
1H d 1.32 %t, Jˆ
1.2.2. Ethyl 5-ꢀ3-aminophenyl)-1-ꢀ5-methyl-2-phenyl-
pyrrol-3-yl)-2-methylpyrrole-3-carboxylate ꢀ8b). Pale-
yellow crystals, yield 91%, mp 219±2218C; 3408 %NH),
7.1 Hz, 3H, CH3), 2.31 %s, 3H, CH3), 2.34 %s, 3H, CH3),
4.25 %q, Jˆ7.1 Hz, 2H, CH2), 5.99 %s, 1H, pyrrole H-40),
6.86 %d, Jˆ7.5 Hz, 2H, H-2 and H-6, 20-Ph), 6.97 %s, 1H,
pyrrole H-4), 7.06 %t, Jˆ7.5 Hz, 1H, H-4, 20-Ph), 7.18 %t,
Jˆ7.5 Hz, 2H, H-3 and H-5, 20-Ph), 7.39 %t, Jˆ8.1 Hz, 1H,
H-50), 7.58 %d, Jˆ8.1 Hz, 1H, H-60), 7.82 %s, 1H, H-20), 7.91
%d, Jˆ8.1 Hz, 1H, H-40), 11.36 %s, 1H, NH); 13C 11.84 %q),
12.73 %q), 14.30 %q), 59.09 %t), 106.75 %d), 110.67 %d), 112.47
%s), 117.31 %s), 120.68 %d), 123.64 %2d), 124.97 %s), 125.89
%d), 128.53 %d), 128.67 %s), 129.25 %d), 130.69 %s), 130.70 %s),
132.97 %d), 133.53 %s), 138.95 %s), 147.44 %s), 164.17 %s);
MS: m/z 429 %M1). Anal. Calcd for C25H23N3O4: C, 69.92;
H, 5.40; N, 9.78. Found: C, 70.02; H, 5.44; N, 9.69.
1
3327 and 3230 %NH2), 1686 %CO) cm21; H d 1.28 %t,
Jˆ7.1 Hz, 3H, CH3), 2.13 %s, 3H, CH3), 2.26 %s, 3H, CH3),
4.19 %q, Jˆ7.1 Hz, 2H, CH2), 4.89 %s, 2H, NH2), 5.82 %s, 1H,
pyrrole H-40), 6.34 %d, Jˆ7.5 Hz, 2H, H-40 and H-60), 6.59
%s, 1H, H-20), 6.60 %s, 1H, pyrrole H-4), 6.76 %t, Jˆ7.5 Hz,
1H, H-50), 6.96 %d, Jˆ7.1 Hz, 2H, H-2 and H-6, 20-Ph), 7.07
%t, Jˆ7.1 Hz, 1H, H-4, 20-Ph), 7.21 %t, Jˆ7.1 Hz, 2H, H-3
and H-5, 20-Ph), 11.12 %s, 1H, NH); 13C 11.68 %q), 12.83 %q),
14.34 %q), 58.82 %t), 107.48 %d), 108.56 %d), 111.61 %s),
112.51 %d), 113.21 %d), 114.86 %d), 118.36 %s), 123.28 %d),
124.54 %s), 125.60 %d), 127.73 %s), 128.27 %d), 128.59 %d),
131.09 %s), 132.76 %s), 134.33 %s), 137.61 %s), 148.16 %s),
164.43 %s); MS: m/z 399 %M1). Anal. Calcd for
C25H25N3O2: C, 75.16; H, 6.31; N, 10.52. Found: C,
74.85; H, 6.32; N, 10.49.
1.1.3. Ethyl 1-ꢀ2-5-diphenylpyrrol-3-yl)-5-ꢀ3-nitrophe-
nyl)pyrrole-3-carboxylate ꢀ7c). Yellow±orange crystals,
yield 70%, mp 104±1068C; 3345±3290 %broad NH), 1682
%CO), 1530 and 1346 %NO2) cm21; 1H d 1.31 %t, Jˆ7.3 Hz,
3H, CH3), 2.42 %s, 3H, CH3), 4.26 %q, Jˆ7.3 Hz, 2H, CH2),
6.86 %s, 1H, pyrrole H-40), 6.94 %d, Jˆ6.8 Hz, 2H, Ph), 6.96
%s, 1H, pyrrole H-4), 7.10±7.30 %m, 4H, Ph), 7.32±7.48 %m,
2H, Ph),7.39 %t, Jˆ7.8 Hz, 1H, H-50), 7.56 %d, Jˆ7.8 Hz,
1H, H-60), 7.78±7.90 %m, 2H, Ph), 7.81 %s, 1H, H-20), 7.90
%d, Jˆ7.3 Hz, 1H, H-40), 11.68 %s, 1H, NH); 13C 12.00 %q),
14.37 %q), 59.20 %t), 106.78 %d), 110.77 %d), 112.63 %s),
118.95 %s), 120.94 %2d), 124.40 %d), 125.06 %d), 126.67 %d),
126.76 %d), 128.21 %s), 128.45 %d), 128.65 %d), 129.38 %d),
130.14 %s), 130.91 %s), 131.62 %s), 132.03 %s),133.16 %d),
133.45 %s), 138.95 %s), 147.42 %s), 164.217 %s); MS: m/z
491.5 %M1). Anal. Calcd for C30H25N3O4: C, 73.30; H,
5.13; N, 8.55. Found: C, 73.10; H, 5.17; N, 8.45.
1.2.3. Ethyl 5-ꢀ3-aminophenyl)-1-ꢀ2,5-diphenylpyrrol-3-
yl)-2-methylpyrrole-3-carboxylate ꢀ8c). Yellow±brown
crystals, yield 70%, mp 146±1488C; 3445 and 3339
1
%NH2), 3200 %NH), 1678 %CO) cm21; H d 1.29 %t, Jˆ
7.3 Hz, 3H, CH3), 2.26 %s, 3H, CH3), 4.21 %q, Jˆ7.3 Hz,
2H, CH2), 4.94 %s, 2H, NH2), 5.75 %s, 1H, CH, pyrrole
H-40), 6.38 %t, Jˆ7.3 Hz, 2H, H-3 and H-5, Ph), 6.66 %s,
1H, pyrrole H-4), 6.68 %d, Jˆ7.9 Hz, 1H, H-40), 6.70 %s,
1H, H-20), 6.78 %t, Jˆ7.9 Hz, 1H, H-50), 7.10±7.38 %m,
6H, H-2 and H-5, Ph), 7.30 %d, Jˆ7.9 Hz, 1H, H-60),
11.52 %s, 1H, NH); 13C 11.84 %q), 14.42 %q), 58.99 %t),
107.64 %d), 108.78 %d), 111.87 %s), 112.68 %d), 113.39 %d),
114.96 %d), 120.07 %s), 124.29 %d), 124.77 %d), 126.50 %d),
126.59 %d), 128.01 %s), 128.44 %d), 128.62 %2d), 130.56 %s),
131.28 %s), 131.75 %s), 132.74 %s), 134.60 %s), 137.72 %s),
148.34 %s), 164.52 %s); MS: m/z 461 %M1). Anal. Calcd for
C30H27N3O2: C, 78.07; H, 5.90; N, 9.10. Found: C, 77.99; H,
5.91; N, 9.04.
1.2. General method for the preparation of 2,5-disub-
stituted ethyl 5-ꢀ3-aminophenyl)-2-methyl-1-ꢀpyrrol-
3yl)-pyrrole-3-carboxylate ꢀ8a±c)
Asolution of nitro derivatives % 7a±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
%8a±c) which were puri®ed by recrystallization from
ethanol.
1.3. General method for the preparation of 2,5-disub-
stituted ethyl 5-ꢀ3-azidophenyl)-2-methyl-1-ꢀpyrrol-3yl)-
pyrrole-3-carboxylate ꢀ9a±c)
To a solution of the amines %8a±c) %10 mmol) in acetic acid
%20 mL) sodium nitrite %690 mg, 10 mmol) in water %20 mL)
was added at 0±58C. 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 ®ltered off, air
dried and recrystallized from ethanol.
1.2.1. Ethyl 5-ꢀ3-aminophenyl)-1-ꢀpyrrol-3-yl)-2-methyl-
pyrrole-20,3-dicarboxylate ꢀ8a). Pale-yellow needles,
yield 90%, mp 177±1788C; 3387 %NH), 3316 and 3210
1
%NH2), 1697 %CO), 1680 %CO) cm21; H d 1.02 %t, Jˆ
7.1 Hz, 3H, CH3), 1.28 %t, Jˆ7.1 Hz, 3H, CH3), 2.23 %s,
3H, CH3), 3.99 %m, 2H, CH2), 4.20 %q, Jˆ7.1 Hz, 2H,
CH2), 4.93 %s, 2H, NH2), 6.19 %d, Jˆ7.8 Hz, 1H, H-40),
6.20 %bs, 1H, H-20), 6.36 %d, Jˆ7.6 Hz, 1H, H-60), 6.49 %s,
1H, pyrrole H-4), 6.50 %s, Jˆ2.4 Hz, 1H, pyrrole H-40), 6.79
%t, Jˆ7.6 Hz, 1H, H-50), 7.06 %d, Jˆ2.4 Hz, 1H, pyrrole
H-50), 11.65 %s, 1H, NH); 13C 11.89 %q), 13.85 %q), 14.48
%q), 58.82 %t), 59.55 %t), 108.00 %d), 110.54 %d), 111.30 %s),
112.56 %d), 113.50 %d), 115.13 %d), 117.85 %s), 122.55 %d),
126.53 %s), 128.27 %d), 133.00 %s), 135.01 %s), 137.99 %s),
148.26 %s), 159.14 %s), 164.71 %s); MS: m/z 381 %M1). Anal.
1.3.1. Ethyl 5-ꢀ3-azidophenyl)-1-ꢀpyrrol-3-yl)-2-methyl-
pyrrole-20,3-dicarboxylate ꢀ9a). Yellow±brown crystals,
yield 85%, mp 79±818C; 3431and 3293 %NH), 2105 %N3),
1686 %CO) cm21; 1H: d 1.00 %t, Jˆ6.7 Hz, 3H, CH3), 1.29 %t,
Jˆ7.1 Hz, 3H, CH3), 2.28 %s, 3H, CH3), 3.98 %m, Jˆ6.7 Hz,
2H, CH2), 4.23 %q, Jˆ7.1 Hz, 2H, CH2), 6.29 %d, Jˆ2.2 Hz,
1H, pyrrole H-40), 6.70±6.77 %bs, 2H, H-20 and pyrrole
H-4), 6.86 %d, Jˆ8.2 Hz, 1H, H-40), 7.04 %d, Jˆ8.2 Hz,
1H, H-60), 7.13 %d, Jˆ2.2 Hz, 1H, pyrrole H-50), 7.25 %t,
Jˆ8.2 Hz, 1H, H-50), 12.29 %s, 1H, NH); 13C 11.84 %q),

10152
F. Mingoia / Tetrahedron 57 ,2001) 10147±10153
13.79 %q), 14.41 %q), 58.90%t), 59.58 %t), 109.28 %d), 110.36
%d), 111.78 %s), 116.88 %d), 117.12 %d), 117.84 %s), 122.93
%d), 123.92 %d), 126.00 %s), 129.70 %d), 132.70 %s), 134.04 %s),
138.88 %s), 139.00 %s), 158.90 %s), 164.40 %s); MS: m/z 381
%M1226). Anal. Calcd for C21H21N5O4: C, 61.91; H, 5.20;
N, 17.19. Found: C, 61.78; H, 5.21; N, 17.13.
7.1 Hz, 1H, H-9), 7.16 %d, Jˆ2.5 Hz, 1H, H-2), 7.26 %s,
1H, H-7), 7.53 %d, Jˆ7.1 Hz, 1H, H-8); 13C 12.97 %q),
14.43 %q), 59.09 %t), 97.15 %d), 101.68 %d), 110.51 %s),
112.82 %s), 113.03 %d), 114.93 %d), 118.33 %s), 119.53 %d),
121.22 %s), 124.18 %s), 125.88 %d), 127.53 %s), 128.36 %s),
142.08 %s), 164.96 %s); MS: m/z 307. Anal. Calcd for
C18H17N3O2: C, 70.34; H, 5.58; N, 13.67. Found: C,
70.26; H, 5.59; N, 13.65.
1.3.2. Ethyl 5-ꢀ3-azidophenyl)-1-ꢀ5-methyl-2-phenyl-
pyrrol-3-yl)-2-methylpyrrole-3-carboxylate ꢀ9b). Pale-
yellow, yield 70%, mp 186±1888C; 3330±3600 %br NH),
In the case of the decomposition of derivative %9b) elution
with dichloromethane/ethyl acetate %95:05) gave ethyl
11-amino-2,5-dimethyl-11bH-11b-phenyl-dipyrrolo[2,1-a:
3,2-c]isoquinoline-6-carboxylate %14b) brown powder,
yield 19%, mp 174±1768C; 3466 and 3310 %NH2), 1695
1
2102 %N3), 1684 %CO) cm21; H d 1.30 %t, Jˆ7.1 Hz, 3H,
CH3), 2.26 %s, 3H, CH3), 2.29 %s, 3H, CH3), 4.22 %q,
Jˆ7.1 Hz, 2H, CH2), 5.92 %s, 1H, pyrrole H-40), 6.76 %bs,
1H, H-20), 6.61 %d, Jˆ7.5 Hz, 1H, H-40), 6.86 %s, 1H, pyrrole
H-4), 6.74±6.94 %m, 2H, H-60 and H-50), 7.01±7.24 %m, 5H,
20-Ph), 11.33 %s, 1H, NH); 13C 11.79 %q), 12.77 %q), 14.33
%q), 58.99 %t), 107.06 %d), 109.83 %d), 112.14 %s), 11.35
%d), 117.04 %d), 117.78 %s), 123.43 %d), 123.69 %d), 124.76
%s), 125.78 %d), 128.39 %s), 128.57 %d), 129.53 %d), 130.80
%s), 131.88 %s), 133.79 %s), 138.52 %s), 138.88 %s), 164.28
%s); MS: m/z 399 %M1226). Anal. Calcd for C25H23N5O2:
C, 70.57; H, 5.45; N, 16.46. Found: C, 70.45; H, 5.47; N,
16.42.
1
%CO) cm21; H d 1.25 %t, Jˆ6.9 Hz, 3H, CH3), 2.37 %s,
3H, CH3), 2.54 %s, 3H, CH3), 4.19 %q, Jˆ6.9 Hz, 2H,
CH2), 6.16 %bs, 2H, NH2), 6.52 %s, 1H, H-3), 6.57 %d,
Jˆ8.1 Hz, H-10), 6.88 %s, 1H, H-7), 6.90±6.97 %m, 2H,
H-2 and H-6, 11b-Ph), 6.92 %d, Jˆ8.1 Hz, 1H, H-8), 7.06
%t, Jˆ8.1 Hz, 1H, H-9), 7.12±7.22 %m, 3H, H-3, H-5 and
H-4, 11b-Ph); 13C 11.41 %q), 14.28 %q), 19.32 %q), 59.36 %t),
84.93 %s), 106.74 %d), 101.46 %d), 113.08 %d), 114.33 %d),
114.96 %s), 115.34 %s), 125.52 %d), 127.63 %d), 127.94 %s),
128.52 %d), 129.07 %d), 130.13 %s), 133.79 %s), 137.42 %s),
147.80 %s), 161.32 %s), 163.84 %s), 174.03 %s); MS: m/z 397.
Anal. Calcd for C25H23N3O3: C, 75.54; H, 5.83; N, 10.57.
Found: C, 75.84; H, 5.86; N, 10.52.
1.3.3. Ethyl 5-ꢀ3-azidophenyl)-1-ꢀ2,5-diphenylpyrrol-3-
yl)-2-methylpyrrole-3-carboxylate ꢀ9c). Pale-yellow
crystals, yield 50%, mp 59±608C; 3323 %NH), 2102 %N3),
1678 %CO) cm21; 1H d 1.31 %t, Jˆ6.8 Hz, 3H, CH3), 2.36 %s,
3H, CH3), 2.12 %s, 3H, CH3), 4.24 %q, Jˆ6.8 Hz, 2H, CH2),
6.79 %s, 1H, pyrrole H-40), 6.78 %m, 1H, H-40), 6.85 %bs, 1H,
H-20), 6.90 %s, 1H, pyrrole H-4), 7.04±7.48 %m, 8H, 20-Ph
and 50-Ph), 7.12±7.20 %m, 2H, H-50 and H-60), 7.86 %d,
Jˆ6.8 Hz, 2H, 50-Ph), 11.63 %s,1H, NH); 13C 11.92 %q),
14.36 %q), 59.10 %t), 107.06 %d), 110.01 %d), 112.38 %s),
116.77 %d), 117.10 %d), 119.49 %s), 123.82 %d), 124.33 %d),
124.91 %d), 126.56 %d), 126.65 %d), 128.13 %s), 128.51 %d),
128.59 %d), 129.56 %d) 130.32 %s), 131.64 %s), 131.79 %s),
132.21 %s), 133.80 %s), 138.55 %s), 138.99 %s), 164.34 %s);
MS: m/z 461 %M1226). Anal. Calcd for C30H25N5O2: C,
73.90; H, 5.17; N, 14.36. Found: C, 74.19; H, 5.19; N, 14.42.
Further elution with dichloromethane/ethyl acetate %95:05)
gave ethyl 9-amino-2,5-dimethyl-11bH-phenyl-dipyrrolo-
[2,1-a:3,2-c]isoquinoline-6-carboxylate %15b): yellow
powder, yield 68%, mp 235±2368C; 3476 and 3337
%NH2), 1697 %CO) cm21
;
1H d 1.27 %t, Jˆ6.7 Hz, 3H,
CH3), 2.31 %s, 3H, CH3), 2.60 %s, 3H, CH3), 4.19 %q, Jˆ
6.7 Hz, 2H, CH2), 5.24 %bs, 2H, NH2), 6.45 %s, 1H, H-3),
6.58 %dd, Jˆ8.1, 1.9 Hz, H-10), 6.89 %s, 1H, H-7), 6.70±6.90
%m, 2H, H-2 and H-6, 11b-Ph), 6.91 %d, Jˆ1.9 Hz, 1H, H-8),
7.08±7.22 %m, 3H, H-3, H-5 and H-4, 11b-Ph), 7.43 %d,
Jˆ8.1 Hz, 1H, H-11); 13C 11.47 %q), 14.24 %q), 19.27 %q),
59.35 %t), 83.67 %s), 105.89 %d), 108.26 %d), 113.40 %d),
113.78 %d), 114.88 %s), 121.09 %s), 125.54 %d), 127.13 %d),
127.24 %s), 128.12 %d), 128.28 %d), 129.92 %s), 134.01 %s),
140.31 %s), 148.55 %s), 161.12 %s), 163.85 %s), 172.81 %s);
MS: m/z 397. Anal. Calcd for C25H23N3O3: C, 75.54; H,
5.83; N, 10.57. Found: C, 75.31; H, 5.86; N, 10.52.
1.4. Decomposition of the azido compounds ꢀ8a±c) in
TFMSA
To a solution of the azido derivatives %9a±c) %6 mmol) in
dry dichloromethane %50 mL) TFMSA%1.8 g, 12 mmol)
was added dropwise at 08C. 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 satu-
rated solution of sodium bicarbonate %150 mL), and
extracted with dichloromethane %4£100 mL). The organic
layer was dried over Na2SO4 and evaporated under reduced
pressure to give a brown residue which was chromato-
graphed.
Compound %13b) due to its instability was only character-
ized by GC±MS and presented a pattern of fragments
in agreement to analogous compounds previously
reported.8,10±11 Dark powder, yield 7%, MS m/z 415.
In the case of the decomposition of derivative %9c) elution
with dichloromethane/ethyl acetate %95:05) gave a ®rst
fraction %25%) which was identi®ed as ethyl 11-amino-5-
methyl-2-phenyl-11bH-phenyl-dipyrrolo[2,1-a:3,2-c]iso-
quinoline-6-carboxylate %14c): yellow-pale powder, yield
25%, mp 212±2138C from DMSO; 3430 and 3326 %NH2),
1696 %CO) cm21; 1H d 1.34 %t, Jˆ7.0 Hz, 3H, CH3), 2.66 %s,
3H, CH3), 4.25 %q, Jˆ7.0 Hz, 2H, CH2), 5.93 %bs, 2H, NH2),
6.60 %d, Jˆ8.2 Hz, H-10), 6.86 %s, 1H, H-3), 6.89 %s, 1H,
H-7), 6.90±7.10 %m, 5H, Ph), 7.10 %t, Jˆ8.2 Hz, 1H, H-9),
7.13 %d, Jˆ8.2 Hz, 1H, H-8), 7.48±7.58 %m, 3H, Ph), 8.05±
8.15 %m, 2H, Ph); 13C 11.38 %q), 13.94 %q), 59.10 %t), 85.21
In the case of the decomposition of derivative %9a) elution
with dichloromethane/ethyl acetate %95:05) gave ethyl 11-
amino-5-methyl-1H-dipyrrolo[2,1-a:3,2-c]isoquinoline-6-
carboxylate %12): white ¯ake, yield 15%, mp 212±2148C;
1
3403 and 3362 %NH2), 3297 %NH), 1682 %CO) cm21; H d
1.34 %t, Jˆ7.1 Hz, 3H, CH3), 3.04 %s, 3H, CH3), 4.27 %q,
Jˆ7.1 Hz, 2H, CH2), 5.23 %bs, 2H, NH2), 6.86 %d, Jˆ
8.3 Hz, H-10), 6.90 %d, Jˆ2.5 Hz, 1H, H-3), 7.12 %d, Jˆ

F. Mingoia / Tetrahedron 57 ,2001) 10147±10153
10153
2. Li, K.; Fernandez-Saiz, M.; Rigl, C. T.; Kumar, A. G.;
G. Ragunathan, K.; McConnaughie, A. W.; Boykin, D. W.;
Shneider, H. J.; Wilson, W. D. Bioorg. Med. Chem. 1997, 5,
1157±1172. Pearson, N. D.; Prescott, C. D. Chem. Biol. 1997,
4, 409.
%s), 106.62 %d), 108.47 %d), 111.55 %d), 114.32 %d), 115.16
%s), 115.65 %s), 125.29 %d), 127.30 %d), 127.43 %d), 127.87 %s),
128.11 %d), 128.29 %d), 128.73 %d), 129.89 %s), 130.88 %d),
132.51 %s), 133.63 %s), 136.85 %s), 147.12 %s), 162.84 %s),
163.86 %s), 171.74 %s); MS: m/z 459. Anal. Calcd for
C30H25N3O2: C, 78.41; H, 5.48; N, 9.14. Found: C, 78.25;
H, 5.50; N, 9.11.
3. Kumar, C. V.; Punzalan, E. H. A.; Tan, W. B. Tetrahedron
2000, 56, 7027±7040.
4. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem.
1988, 31, 774.
Further elution with dichloromethane/ethyl acetate
%95:05) gave ethyl 9-amino-5-methyl-2-phenyl-11bH-phenyl-
5. Nakanishi, T.; Suzuki, M. J. Nat. Prod. 1998, 61, 1263±1267.
6. Suzuki, M.; Nakanishi, T.; Kogawa, O.; Ishikawa, K.;
Kobayashi, F.; Ekimoto H. Eur. Pat. Appl. EP., 487,930,
1992, JP Appl. 90/299,844; Chem. Abstr., 1992, 117,
191706b.
dipyrrolo[2,1-a:3,2-c]isoquinoline-6-carboxylate
yellow±brown powder, yield 35%, mp 158±1608C; 3464
%15c):
and 3379 %NH2), 1694 %CO) cm21
;
1H: d 1.29 %t, Jˆ
7.0 Hz, 3H, CH3), 2.73 %s, 3H, CH3), 4.22 %q, Jˆ7.0 Hz,
2H, CH2), 5.28 %bs, 2H, NH2), 6.63 %d, Jˆ8.8 Hz, H-10),
6.82 %s, 1H, H-3), 6.88±6.97 %m, 2H, Ph), 6.93 %d, Jˆ8.8 Hz,
1H, H-11), 6.96 %s, 1H, H-8), 7.12±7.22 %m, 3H, Ph), 7.30 %s,
1H, H-7), 7.50±7.62 %m, 4H, Ph), 8.17±8.22 %m, 2H, Ph);
13C 11.62 %q), 14.29 %q), 59.43 %t), 84.13 %s), 106.06 %d),
108.39 %d), 110.85 %d), 113.49 %d), 115.01 %s), 121.00 %s),
125.62 %d), 127.32 %s), 127.36 %d), 127.81 %d), 128.22 %d),
128.49 %d), 128.78 %d), 129.94 %s), 131.14 %d), 133.37 %s),
134.36 %s), 140.22 %s), 148.75 %s), 162.27 %s), 163.89 %s),
171.62 %s); MS: m/z 459. Anal. Calcd for C30H25N3O2: C,
78.41; H, 5.48; N, 9.14. Found: C, 78.26; H, 5.49; N, 9.11.
7. Nakanishi, T.; Suzuki, M.; Saimoto, A.; Kabasawa, T. J. Nat.
Prod. 1999, 62, 864±867.
8. Aiello, E.; Dattolo, G.; Cirrincione, G.; Almerico, A. M.;
Grimaudo, S.; Mingoia, F.; Barraja, P. Il Farmaco 1995, 50,
365±368.
9. Burckhardt, G.; Walter, A.; Triebel, H.; Storl, K.; Simon, H.;
Storl, J.; Opitz, A.; Roemer, E.; Zimmer, C. Biochemistry
1998, 37, 4703±4711.
10. Almerico, A. M.; Cirrincione, G.; Diana, P.; Grimaudo, S.;
Dattolo, G.; Aiello, E.; Mingoia, F.; Barraja, P. Heterocycles
1994, 37, 1549±1559.
11. Almerico, A. M.; Cirrincione, G.; Dattolo, G.; Aiello, E.;
Mingoia, F. J. Heterocycl. Chem. 1994, 31, 193±198.
12. Mingoia, F.; Diana, P.; Barraja, P.; Lauria, A.; Almerico, A. M.
Heterocycles 2000, 53, 1975±1985.
Acknowledgements
Agrateful acknowledgement is addressed to the entire
research group of Dipartimento Farmacochimico Tossico-
logico e Biologico %Palermo University, Italy) directed by
Professor G. Cirrincione for valuable discussions and
Á
Professor L. Monsu Scolaro %Messina University, Italy)
for instrumental support.
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8412.
14. Cirrincione, G.; Almerico, A. M.; Aiello, E.; Dattolo, G.
Aminopyrroles in the Chemistry of Heterocyclic Compounds.
Pyrroles Part II; Jones, R. A., Ed.; Wiley: New York, 1992;
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