Synthesis of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one

Article abstract of DOI:10.1016/j.tet.2011.03.060

Derivatives of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one were prepared in four steps starting from substituted benzonitriles bearing a functionalized amino group in the adjacent position. The unsubstituted- and the dimethoxy-pyrrolizinoindolon

Full text of DOI:10.1016/j.tet.2011.03.060

Tetrahedron 67 (2011) 3374e3379
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one
*
Patrizia Diana , Antonina Stagno, Paola Barraja, Alessandra Montalbano, Anna Carbone, Barbara Parrino,
Girolamo Cirrincione
ꢀ
Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, Sezione Chimica Farmaceutica e Biologica, Universita degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Derivatives of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one were prepared in four steps
starting from substituted benzonitriles bearing a functionalized amino group in the adjacent position.
The unsubstituted- and the dimethoxy-pyrrolizinoindolones 5a and 5b exhibited modest activity against
the HL-60(TB) human leukemia cell line, whereas the N-methylated dimethoxy-pyrrolizinoindolone 6b
showed to be selective against MOLT-4 leukemia, A549/ATCC, HOP-92, and NCI-H460 non-small cell lung
cancer, and CAKI-1 renal cancer cell lines.
Received 22 December 2010
Received in revised form 3 March 2011
Accepted 21 March 2011
Available online 26 March 2011
Keywords:
Pyrrolizino[2,3-b]indol-4(5H)-one
Tripentone
Ó 2011 Elsevier Ltd. All rights reserved.
Antitumor activity
Antitubulin agents
1. Introduction
X
Y
O
1 X=S, Y=CH;
Cancer is a growing public problem estimated to have around
seven million new incidences per year worldwide. Research toward
the discovery of agents useful in cancer chemotherapy has identified
tubulin as a possible molecular target. Molecules that interact with
tubulin, the protein subunit of microtubules, cause mitotic arrest,
interfering withthe dynamicequilibrium oftheseorganelleseither by
inhibiting tubulin polymerization or blocking microtubule disas-
sembly. Many natural andsyntheticsubstancesareknowntointerfere
with the dynamic assembly of tubulin and prevent the formation of
microtubules, which are essential for cellular integrity and cell di-
vision.Microtubulesareawell-validatedtargetforanticancertherapy.
Currently, the most used among the antitubulin agents are
natural products, such as paclitaxel,1 vinca alkaloids,2 colchicine,3
and combretastatin A-4.4
A series of substituted heterocyclic ketones based on the ‘tri-
pentone’ skeleton of thieno[2,3-b]pyrrolizin-8-ones of type 1
showed a remarkable cytostatic activity over all the tested lines
with the highest effect against leukemia, central nervous system,
ovarian, and breast cancers.5
In order to specify structural requirements, novel tripentone
derivatives based on the bio-isosteric replacementof the sulfuratom
were synthesized. In fact the thiophene moiety was replaced by
a pyrrole (2), pyrazole (3), or furan (4) ring (Fig.1). Most of these new
derivatives exhibited interesting cytotoxic properties associated to
an anti-tubulin effect and a cyclin-dependent kinase inhibition.6
2 X=NH, Y=CH;
3 X=NH, Y=N;
4 X=O, Y=CH;
Ar
N
R
N
O
5 R=H,
6 R=CH3
N
Fig. 1. ‘Tripentone’ structures.
Considering the interesting results of this class of compounds,
and with the aim of searching for novel promising antimitotic
agents, we focused our attention on the synthesis of new hetero-
pyrrolizinone systems.
Herein we describe the synthesis of the new ring system pyr-
rolizino[2,3-b]indol-4(5H)-one 5, in which the indole nucleus re-
places the thiophene ring, and the antiproliferative activity of the
new derivatives was investigated.
2. Results and discussion
Pyrrolizino[2,3-b]indolones 5aeg were prepared in four steps
starting from 2-carbamoyl benzonitriles 7beg or carbon-
ylmethylamino benzonitrile 7a. Thus 7beg, prepared from substituted
aminobenzonitriles in refluxing ethyl chloroformate,7 were in turn
* Corresponding author. Tel.: þ39 091 6161606; fax: þ39 091 23860854; e-mail
address: diana@unipa.it (P. Diana).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.060

P. Diana et al. / Tetrahedron 67 (2011) 3374e3379
3375
converted into the 3-amino-substituted-1H-1,2-indole-dicarboxylates
8beg, in good to excellent yields (70e96%) by action of ethyl bro-
moacetate using NaH as base, in DMF, followed by intramolecular
cyclization.
Alternatively 3-amino-1H-indole-2-carboxylate 8a was pre-
pared, in high yield (90%), from 2-aminobenzonitrile 7a and ethyl
bromoacetate by reaction with t-BuOK.8
Reaction of 3-amino-substituted-indoles 8aeg with 2,5-dime-
thoxytetrahydrofuran and4-chloropyridinehydrochloridein dioxan,
through a modified ClausoneKaas reaction, gave 3-pyrrolyl-indolo-
2-carboxylates 9aeg (78e91% yields). These latter led, in refluxing
pyrrolidine, to the corresponding indole-2-carboxamides 10aeg
(81e97% yields). In this step, the original reaction conditions (basic
medium andtemperature)favorhydrolysisof theestermoietybound
to the indole nitrogen to form the carbamic acid. The following de-
carboxylation gives the 1-unsubstituted indoles (Scheme 1).
Biological screenings were performed, on nine pyrrolizi-
noindolones (5a, 5b, 5c, 5d, 5e, 6b, 6c, 6d, 6e), selected by the
National Cancer Institute (Bethesda, MD), at one dose concentra-
tion (10ꢀ5 M), for the in vitro disease-oriented antitumor screen-
ings against a panel of about 60 human tumor cell lines grouped in
disease sub-panel including leukemia, non-small lung, colon, cen-
tral nervous system, melanoma, ovarian, renal, prostate, and breast
tumors cell lines.9 The results obtained take into consideration the
growth inhibitory power (GI50).
The unsubstituted- and the dimethoxy-pyrrolizinoindolones 5a
and 5b exhibited modest activity against the HL-60(TB) of the
leukemia sub-panel.
More interesting results were obtained from the dimethoxy-N-
methyl-pyrrolizinoindolones 6b, which showed to be selective
against the MOLT-4 of leukemia sub-panel, the A549/ATCC, HOP-
92, and NCI-H460 of non-small cell lung cancer sub-panel, and the
CAKI-1 of renal cancer sub-panel cell lines.
R1
R2
NHCO2Et
CN
NHCH2CO2Et
CN
3. Conclusions
In conclusion, we have reported a versatile method, which al-
lows the synthesis of derivatives of the new ring system pyrrolizino
[2,3-b]indol-4(5H)-one of type 5 and 6 in good overall yields
(52e72%). Three derivatives of this series showed antitumor ac-
tivity against some tumors cell lines at micromolar concentrations.
R3
7a
7b-g
i
ii
R
N
R
N
4. Experimental section
4.1. General
R1
R2
R1
R2
iii
CO2Et
CO2Et
NH2
R3
N
R3
€
All melting points were taken on a BuchieTottoli capillary appa-
8a-g
9a-g
ratus andare uncorrected; IR spectrawere 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 or
CDCl3 solution, usinga Bruker Avance IIseries 200 MHz spectrometer
(TMS as internal reference). Column chromatography was performed
iv
H
H
N
6
7
8
R1
R2
R1
R2
N 5
€
with Merck silica gel 230e400 mesh ASTM or with Buchi Sepacore
O
v
CO
N
chromatography module (prepacked cartridge system). Elemental
analyses (C, H, N) were within ꢁ0.4% of the theoretical values.
4
9
R3
N
N
R3
3
1
5a-g
10a-g
4.2. General method for the synthesis of diethyl 3-amino-1H-
indole-1,2-dicarboxylates 8beg
2
vi
To a stirred solution of the appropriate N-ethoxycarbonylaniline
7beg (2 mmol) in DMF (5 mL), sodium hydride (192 mg, 60% dis-
persed in mineral oil, 4 mmol) was added. The mixture was stirred
for 1 h, then ethyl bromoacetate (2 mmol, 0.22 mL) was added and
the resulting mixture was stirred at room temperature for 22 h. The
reaction mixture was poured into ice and washed with water, and
the precipitate was filtered off, air dried, and purified by chroma-
tography column using dichloromethane as eluant to afford 3-
amino-1H-indole-1,2-dicarboxylates 8beg.
a R=R1=R2=R3=H;
CH3
N
R1
R2
b R=CO2Et, R1=R2=OCH3, R3=H;
c R=CO2Et, R1=R3=H, R2=Cl;
d R=CO2Et, R1=R2=H, R3=Cl;
e R=CO2Et, R2=R3=H, R1=Cl;
f R=CO2Et, R1=R2=H, R3=CH3;
g R=CO2Et, R1=CH3, R2=R3=H
O
N
R3
6a-g
Scheme 1. Reagents and conditions. (i) NaH/DMF rt, 1 h, then ethyl bromoacetate rt,
22 h, 70e96% yields; (ii) t-BuOK/THF, rt, 2 h, 90% yield; (iii) 2,5-dimethoxytetrahy-
drofuran/dioxan, 4-chloropyridine hydrochloride, rt, 15 min, then reflux 1e4 h,
78e91% yields; (iv) pyrrolidine, reflux 18 h, 81e97% yields; (v) POCl3/DMF, 70 ꢂC,
3e7 h, 88e98% yields; (vi) t-BuOK/toluene, TDA-1, rt, 5e6 h, then CH3I, rt, 18 h, 72e84%
yields.
4.2.1. Diethyl 3-amino-5,6-dimethoxy-1H-indole-1,2-dicarboxylate
(8b). Yellow oil, yield 96%. IR: 3465 and 3361 (NH2), 1711 (CO), 1660
(CO) cmꢀ1
.
1H NMR (CDCl3):
d
1.36 (t, J¼7.2 Hz, 3H, CH3), 1.38 (t,
J¼7.2Hz,3H,CH3), 3.92(s, 3H,CH3), 3.97(s, 3H,CH3), 4.34(q, J¼7.2Hz,
Cyclization of indole-2-carboxamides 10aeg was performed, in
excellent yields, under VielsmeiereHaack conditions by action of
phosphorus oxychloride and dimethylformamide to give, via an
intermediate iminium salt subsequently hydrolyzed in alkaline
conditions, the new ring system pyrrolizinoindolones 5aeg
(88e98% yields). Treatment of the tetracyclic derivatives 5beg with
t-BuOK as the base, tris(2-(2-methoxyethoxy)ethyl)amine (TDA-1)
as catalyst and methyl iodide in toluene yielded the corresponding
N-methyl-pyrrolizinoindolones 6beg in good yields (72e90%).
2H, CH2), 4.38 (q, J¼7.2 Hz, 2H, CH2), 5.16 (br s, 2H, NH2), 6.88 (s, 1H,
CH), 7.65(s,1H, CH).13C NMR (CDCl3):
d 14.3(q),14.6 (q), 56.2 (q), 56.3
(q), 60.1 (t), 63.1 (t), 98.6 (d), 99.9 (d), 104.4 (s), 114.0 (s), 134.0 (s),
142.3 (s), 146.6 (s), 151.7 (s), 152.5 (s), 162.8 (s). Anal. Calcd for
C16H20N2O6: C, 57.14; H, 5.99;N, 8.33. Found: C, 57.48; H, 6.13; N, 8.09.
4.2.2. Diethyl 3-amino-5-chloro-1H-indole-1,2-dicarboxylate (8c).
Yellow solid from ethanol, mp 77e78 ꢂC, yield 86%. IR: 3469 and 3363
(NH2), 1730 (CO), 1659 (CO) cmꢀ1. 1H NMR (CDCl3):
d
1.37 (t, J¼7.1 Hz,

3376
P. Diana et al. / Tetrahedron 67 (2011) 3374e3379
3H, CH3),1.39 (t, J¼7.1 Hz, 3H, CH3), 4.36 (q, J¼7.1 Hz, 2H, CH2), 4.40 (q,
J¼7.1 Hz, 2H, CH2), 5.11 (br s, 2H, NH2), 7.40 (dd, J¼8.9, 2.1 Hz,1H, CH),
7.47 (d, J¼2.1 Hz, 1H, CH), 7.98 (d, J¼8.9 Hz, 1H, CH). 13C NMR (CDCl3):
4.3.1. Ethyl 3-(1H-pyrrol-1-yl)-1H-indole-2-carboxylate (9a). White
solid from ethanol, mp 114e115 ꢂC, yield 91%. IR: 3437 and 3325
(NH), 1682 (CO). 1H NMR (CDCl3):
d
1.29 (t, J¼7.1 Hz, 3H, CH3), 4.33
d
14.2 (q), 14.5 (q), 60.5 (t), 63.4 (t), 108.4 (s), 116.8 (d), 118.6 (d), 123.2
(q, J¼7.1 Hz, 2H, CH2), 6.35 (d, J¼2.1 Hz, 2H, 2ꢃCH), 6.98 (d,
(s), 128.4 (s), 129.1 (d), 136.6 (s), 140.3 (s), 151.8 (s), 162.6 (s). Anal.
Calcd for C14H15ClN2O4: C, 54.11; H, 4.87; N, 9.02. Found: C, 54.36; H,
4.62; N, 9.29.
J¼2.1 Hz, 2H, 2ꢃCH), 7.12e7.67 (m, 4H, Ar), 9.12 (br s, 1H, NH). 13C
NMR (CDCl3):
d
14.1 (q), 61.3 (t), 108.6 (dꢃ2), 112.0 (d), 119.4 (s),
120.4 (d), 121.4 (d), 123.3 (dꢃ2), 123.7 (s), 124.4 (s), 126.4 (d), 134.3
(s), 161.0 (s). Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02
Found: C, 70.64; H, 5.69; N, 11.29.
4.2.3. Diethyl 3-amino-4-chloro-1H-indole-1,2-dicarboxylate (8d).
Yellow solid from ethanol, mp 81e82 ꢂC, yield 75%. IR: 3500 and
4.3.2. Diethyl 5,6-dimethoxy-3-(1H-pyrrol-1-yl)-1H-indole-1,2-di-
3375 (NH2), 1732 (CO), 1670 (CO) cmꢀ1. 1H NMR (CDCl3):
d 1.36 (t,
carboxylate (9b). White solid from ethanol, mp 95e97 ꢂC, yield 88%.
J¼7.2 Hz, 3H, CH3), 1.38 (t, J¼7.2 Hz, 3H, CH3), 4.35 (q, J¼7.2 Hz, 2H,
CH2), 4.39 (q, J¼7.2 Hz, 2H, CH2), 5.86 (br s, 2H, NH2), 7.14 (dd, J¼7.9,
0.8 Hz, 1H, CH), 7.33 (t, J¼7.9 Hz, 1H, CH), 7.97 (dd, J¼7.9, 0.8 Hz, 1H,
IR: 1736 (CO),1716 (CO) cmꢀ1.1H NMR (CDCl3):
d
1.25 (t, J¼7.1 Hz, 3H,
CH3), 1.44 (t, J¼7.1 Hz, 3H, CH3), 3.88 (s, 3H, CH3), 3.99 (s, 3H, CH3),
4.26(q, J¼7.1 Hz, 2H, CH2), 4.47 (q, J¼7.1 Hz, 2H, CH2), 6.36 (t, J¼1.9 Hz,
2H, 2ꢃCH), 6.92 (s, 1H, CH), 7.03 (d, J¼1.9 Hz, 2H, 2ꢃCH), 7.74 (s, 1H,
CH). 13C NMR (CDCl3):
d 14.2 (q), 14.5 (q), 60.3 (t), 63.5 (t), 106.8 (s),
114.0 (d), 118.6 (s), 123.6 (d), 127.42 (s), 129.2 (d), 139.8 (s), 141.7 (s),
151.9 (s), 162.8 (s). Anal. Calcd for C14H15ClN2O4: C, 54.11; H, 4.87; N,
9.02. Found: C, 54.40; H, 4.74; N, 8.75.
CH).13C NMR(CDCl3):
d13.9 (q),14.1(q), 56.1 (q), 56.2 (q), 61.8(t), 64.1
(t), 98.2 (d), 100.3 (d), 109.4 (dꢃ2), 117.5 (s), 121.0 (s), 122.8 (dꢃ2),
127.1 (s),130.0 (s),147.7 (s),150.6 (s),150.8 (s),161.1 (s). Anal. Calcd for
C20H22N2O6: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.23; H, 5.88; N, 7.17.
4.2.4. Diethyl 3-amino-6-chloro-1H-indole-1,2-dicarboxylate (8e).
Yellow solid from ethanol, mp 72e73 ꢂC, yield 70%. IR: 3479 and
4.3.3. Diethyl 5-chloro-3-(1H-pyrrol-1-yl)-1H-indole-1,2-dicarbox-
ylate (9c). White solid from ethanol, mp 114e115 ꢂC, yield 78%. IR:
3367 (NH2), 1730 (CO), 1670 (CO) cmꢀ1. 1H NMR (CDCl3):
d 1.37 (t,
1740 (CO) cmꢀ1. 1H NMR (CDCl3):
d
1.27 (t, J¼7.1 Hz, 3H, CH3), 1.45 (t,
J¼7.1 Hz, 3H, CH3), 1.40 (t, J¼7.1 Hz, 3H, CH3), 4.36 (q, J¼7.1 Hz, 2H,
CH2), 4.41 (q, J¼7.1 Hz, 2H, CH2), 5.17 (br s, 2H, NH2), 7.21 (dd, J¼8.4,
1.8 Hz, 1H, CH), 7.42 (d, J¼8.4 Hz, 1H, CH), 8.07 (d, J¼1.8 Hz, 1H, CH).
J¼7.1 Hz, 3H, CH3), 4.31 (q, J¼7.1 Hz, 2H, CH2), 4.50 (q, J¼7.1 Hz, 2H, CH2),
6.36 (d, J¼2.1 Hz, 2H, 2ꢃCH), 6.99 (d, J¼2.1 Hz, 2H, 2ꢃCH), 7.41 (dd,
J¼8.9, 2.1 Hz, 1H, CH), 7.56 (d, J¼2.1 Hz, 1H, CH), 8.10 (d, J¼8.9 Hz, 1H,
13C NMR (CDCl3):
d 14.2 (q), 14.5 (q), 60.4 (t), 63.5 (t), 107.7 (s), 115.8
CH). 13C NMR (CDCl3):
116.7 (d), 119.3 (d), 122.6 (dꢃ2), 124.0 (s), 124.9 (s), 126.2 (s), 127.8 (d),
130.0 (s), 132.9 (s), 150.2 (s), 161.0 (s). Anal. Calcd for C18H17ClN2O4: C,
59.62; H, 4.75; N, 7.76. Found: C, 59.28; H, 4.59; N, 7.82.
d
13.9 (q), 14.1 (q), 62.3 (t), 64.5 (t), 109.9 (dꢃ2),
(d), 119.8 (d), 120.6 (s), 123.4 (d), 135.1 (s), 138.7 (s), 140.9 (s), 151.8
(s), 162.6 (s). Anal. Calcd for C14H15ClN2O4: C, 54.11; H, 4.87; N, 9.02.
Found: C, 53.89; H, 5.22; N, 9.33.
4.2.5. Diethyl 3-amino-4-methyl-1H-indole-1,2-dicarboxylate (8f).
Yellow solid from ethanol, mp 75e76 ꢂC, yield 80%. IR: 3504 and
4.3.4. Diethyl 4-chloro-3-(1H-pyrrol-1-yl)-1H-indole-1,2-dicarbox-
ylate (9d). White solid from ethanol, mp 100e101 ꢂC, yield 89%. IR:
3369 (NH2), 1725 (CO), 1666 (CO) cmꢀ1. 1H NMR (CDCl3):
d 1.36 (t,
1737 (CO) cmꢀ1. 1H NMR (CDCl3):
d
1.17 (t, J¼7.1 Hz, 3H, CH3), 1.44 (t,
J¼6.9 Hz, 3H, CH3), 1.39 (t, J¼6.9 Hz, 3H, CH3), 2.71 (s, 3H, CH3), 4.34
(q, J¼6.9 Hz, 2H, CH2), 4.37 (q, J¼6.9 Hz, 2H, CH2), 5.43 (br s, 2H, NH2),
6.93 (d, J¼8.0 Hz,1H, CH), 7.31 (t, J¼8.0 Hz,1H, CH), 7.90 (d, J¼8.0 Hz,
J¼7.1 Hz, 3H, CH3), 4.22(q, J¼7.1 Hz, 2H, CH2), 4.50(q, J¼7.1 Hz, 2H, CH2),
6.29 (d, J¼2.1 Hz, 2H, 2ꢃCH), 6.80 (d, J¼2.1 Hz, 2H, 2ꢃCH), 7.26 (dd,
J¼7.9, 1.0 Hz, 1H, CH), 7.37 (t, J¼7.9Hz,1H,CH),8.13(dd,J¼7.9, 1.0 Hz, 1H,
1H, CH).13C NMR (CDCl3):
d 14.3 (q),14.5 (q),19.7 (q), 60.2 (t), 63.1 (t),
CH). 13C NMR (CDCl3):
d
13.8 (q), 14.0 (q), 62.2 (t), 64.7 (t), 108.9 (dꢃ2),
106.8 (s), 113.1 (d), 120.7 (s), 124.6 (d), 128.9 (d), 132.2 (s), 139.0 (s),
143.8 (s), 152.2 (s), 163.2 (s). Anal. Calcd for C15H18N2O4: C, 62.06; H,
6.25; N, 9.65. Found: C, 62.34; H, 6.11; N, 9.87.
113.9 (d), 122.5 (s), 124.4 (dꢃ2), 124.5 (s), 125.3 (d), 126.4 (s), 127.6 (d),
128.1 (s), 135.5 (s), 149.9 (s), 160.6 (s). Anal. Calcd for C18H17ClN2O4: C,
59.62; H, 4.75; N, 7.76. Found: C, 59.34; H, 4.96; N, 7.43.
4.2.6. Diethyl 3-amino-6-methyl-1H-indole-1,2-dicarboxylate (8g).
4.3.5. Diethyl 6-chloro-3-(1H-pyrrol-1-yl)-1H-indole-1,2-dicarbox-
Yellow oil, yield 82%. IR: 3456 and 3369 (NH2), 1726 (CO), 1676
ylate (9e). White solid from ethanol, mp 77e78 ꢂC, yield 85%. IR: 1733
(CO) cmꢀ1
.
1H NMR (CDCl3):
d
1.32 (t, J¼7.1 Hz, 3H, CH3), 1.43 (t,
(CO) cmꢀ1.1HNMR(CDCl3):
d
1.28 (t, J¼7.1 Hz, 3H, CH3),1.46 (t, J¼7.1 Hz,
J¼7.1 Hz, 3H, CH3), 2.43 (s, 3H, CH3), 4.27 (q, J¼7.1 Hz, 2H, CH2), 4.40
(q, J¼7.1 Hz, 2H, CH2), 5.19 (br s, 2H, NH2), 7.07 (dd, J¼8.0, 0.6 Hz,1H,
CH), 7.38 (d, J¼8.0 Hz, 1H, CH), 7.88 (d, J¼0.6 Hz, 1H, CH). 13C NMR
3H, CH3), 4.30 (q, J¼7.1 Hz, 2H, CH2), 4.51 (q, J¼7.1 Hz, 2H, CH2), 6.36 (d,
J¼2.2 Hz, 2H, 2ꢃCH), 7.01 (d, J¼2.2 Hz, 2H, 2ꢃCH), 7.29 (dd, J¼8.5,
1.8 Hz,1H, CH), 7.52 (d, J¼8.5 Hz,1H, CH), 8.19 (d, J¼1.8 Hz, 1H, CH). 13C
(CDCl3): d 14.3 (q), 14.5 (q), 22.3 (q), 60.2 (t), 63.1 (t), 106.7 (s), 115.6
NMR (CDCl3):
d
13.9 (q),14.1 (q), 62.3 (t), 64.6 (t),109.8 (dꢃ2),115.7 (d),
(d), 118.5 (d), 119.8 (s), 124.2 (d), 136.9 (s), 139.9 (s), 141.9 (s), 152.4
(s), 163.0 (s). Anal. Calcd for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65.
Found: C, 61.95; H, 6.58; N, 9. 41.
120.7 (d), 122.6 (dꢃ2), 123.1 (s), 123.5 (s), 124.8 (d), 125.7 (s), 133.6 (s),
134.9 (s), 150.2 (s), 161.0 (s). Anal. Calcd for C18H17ClN2O4: C, 59.62; H,
4.75; N, 7.76. Found: C, 59.88; H, 4.79; N, 8.03.
4.3. General method for the synthesis of substituted ethyl 3-
(1H-pyrrol-1-yl)-1H-indole-2-carboxylates (9aeg)
4.3.6. Diethyl 4-methyl-3-(1H-pyrrol-1-yl)-1H-indole-1,2-dicarbox-
ylate (9f). White solid from ethanol, mp 62e63 ꢂC, yield 87%. IR:
1737 (CO) cmꢀ1. 1H NMR (CDCl3):
d
1.15 (t, J¼7.1 Hz, 3H, CH3), 1.44 (t,
A solution of 2,5-dimethoxytetrahydrofuran (0.14 mL, 1.1 mmol)
in dioxan (10 mL), was stirred for 15 min with 4-chloropyridine
hydrochloride (165 mg, 1.1 mmol). The appropriate 3-aminoindole
(8aeg) (1.1 mmol) was added and the reaction mixture was
refluxed for 1e4 h and, then filtered through a small pad of Celite.
The solvent was evaporated to give a brown residue that was dis-
solved in dichloromethane (100 mL). The solution was washed with
a 1 M aqueous hydrochloric acid solution. The organic layer was
dried (Na2SO4) and evaporated to give a crude solid, which was
purified by chromatography column using dichloromethane as el-
uant, to give 3-(1H-pyrrol-1-yl)-indoles (9aeg).
J¼7.1 Hz, 3H, CH3), 1.98 (s, 3H, CH3), 4.20 (q, J¼7.1 Hz, 2H, CH2), 4.48
(q, J¼7.1 Hz, 2H, CH2), 6.30 (d, J¼2.0 Hz, 2H, 2ꢃCH), 6.78 (d,
J¼2.0 Hz, 2H, 2ꢃCH), 7.03 (d, J¼7.9 Hz, 1H, CH), 7.34 (t, J¼7.9 Hz, 1H,
CH), 8.03 (d, J¼7.9 Hz, 1H, CH). 13C NMR (CDCl3):
d 13.8 (q), 14.1 (q),
16.41 (q), 61.9 (t), 64.3 (t), 109.2 (dꢃ2), 112.8 (d), 124.0 (dꢃ2), 124.3
(s), 125.7 (d), 126.5 (s), 126.9 (s), 127.2 (d), 131.8 (s), 134.8 (s), 150.4
(s), 160.9 (s). Anal. Calcd for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23.
Found: C, 66.85; H, 6.02; N, 8.12.
4.3.7. Diethyl 6-methyl-3-(1H-pyrrol-1-yl)-1H-indole-1,2-dicarbox-
ylate (9g). White solid from ethanol, mp 72e73 ꢂC, yield 88%. IR:

P. Diana et al. / Tetrahedron 67 (2011) 3374e3379
3377
1731 (CO) cmꢀ1. 1H NMR (CDCl3):
d
1.27 (t, J¼7.1 Hz, 3H, CH3),1.45 (t,
(s), 135.8 (s), 161.5 (s). Anal. Calcd for C17H16ClN3O: C, 65.07; H, 5.14;
N, 13.39. Found: C, 65.41; H, 5.28; N, 13.30.
J¼7.1 Hz, 3H, CH3), 2.51 (s, 3H, CH3), 4.28 (q, J¼7.1 Hz, 2H, CH2), 4.48
(q, J¼7.1 Hz, 2H, CH2), 6.35 (d, J¼2.1 Hz, 2H, 2ꢃCH), 7.04 (d, J¼2.1 Hz,
2H, 2ꢃCH), 7.14 (dd, J¼8.2, 0.8 Hz,1H, CH), 7.47 (d, J¼8.2 Hz,1H, CH),
4.4.5. [6-Chloro-3-(1H-pyrrol-1-yl)-1H-indol-2-yl]-(pyrrolidin-1-yl)
7.99 (d, J¼0.8 Hz, 1H, CH). 13C NMR (CDCl3):
d
13.9 (q), 14.1 (q), 22.2
methanone (10e). White solid from ethanol, mp 198e199 ꢂC, yield
(q), 62.0 (t), 64.1 (t), 109.4 (dꢃ2), 115.4 (d), 119.5 (d), 121.8 (s), 122.6
(s), 122.7 (dꢃ2), 125.6 (d), 126.5 (s), 135.3 (s), 138.2 (s), 150.7 (s),
161.4 (s). Anal. Calcd for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23.
Found: C, 67.27; H, 5.71; N, 7.99.
97%. IR: 3222 (NH), 1594 (CO) cmꢀ1 1H NMR (CDCl3):
. d 1.65 (q,
J¼6.6 Hz, 2H, CH2), 1.85 (q, J¼6.6 Hz, 2H, CH2), 2.59 (t, J¼6.6 Hz, 2H,
CH2), 3.68 (t, J¼6.6 Hz, 2H, CH2), 6.36 (t, J¼2.1 Hz, 2H, 2ꢃCH), 6.93 (t,
J¼2.1 Hz, 2H, 2ꢃCH), 7.11 (dd, J¼8.6, 1.8 Hz, 1H, CH), 7.50 (d,
J¼1.8 Hz, 1H, CH), 7.57 (d, J¼8.6 Hz, 1H, CH), 10.55 (br s, 1H, NH). 13C
4.4. General method for the synthesis of pyrrolidin-1-yl[3-
(1H-pyrrol-1-yl)-1H-indol-2-yl]methanones (10aeg)
NMR (CDCl3):
d
24.0 (t), 26.0 (t), 46.5 (t), 46.6 (t), 110.1 (dꢃ2), 112.1
(d), 118.8 (s), 120.1 (d), 121.6 (s), 121.7 (dꢃ2), 121.8 (d), 124.0 (s),
130.7 (s), 134.8 (s), 161.8 (s). Anal. Calcd for C17H16ClN3O: C, 65.07;
H, 5.14; N, 13.39. Found: C, 65.34; H, 4.87; N, 12.91.
A solution of the appropriate ethyl 3-(1H-pyrrol-1-yl)-1H-in-
dole-2-carboxylate 9aeg (1 mmol) in pyrrolidine (4 mL) was
refluxed for 18 h. The resulting mixture was cooled and evaporated
under reduced pressure, the yellow oil was crystallized by washing
with diethyl ether and the residue was filtered and purified by
chromatography column using dichloromethane/ethyl acetate (9:1)
as eluant to afford indole-2-carboxamides 10aeg.
4.4.6. [4-Methyl-3-(1H-pyrrol-1-yl)-1H-indol-2-yl]-(pyrrolidin-1-yl)
methanone (10f). White solid from ethanol, mp 174e175 ꢂC, yield81%.
IR: 3241 (NH), 1594 (CO) cmꢀ1. 1H NMR (CDCl3):
d 1.66e1.84 (m, 4H,
2ꢃCH2), 2.15 (s, 3H, CH3), 2.67 (t, J¼6.8 Hz, 2H, CH2), 3.63 (t, J¼6.8 Hz,
2H, CH2), 6.27 (t, J¼2.1 Hz, 2H, 2ꢃCH), 6.82 (t, J¼2.1 Hz, 2H, 2ꢃCH), 6.87
(d, J¼8.2 Hz 1H, CH), 7.20 (d, J¼8.2Hz,1H, CH), 7.30 (t, J¼8.2 Hz 1H, CH),
4.4.1. Pyrrolidin-1-yl[3-(1H-pyrrol-1-yl)-1H-indol-2-yl] methanone
10.10 (s, 1H, NH). 13C NMR (CDCl3):
d 18.2 (q), 23.8 (t), 26.1 (t), 46.7 (t),
(10a). White solid fromethanol, mp 178e180 ꢂC with dec, yield 87%.
47.0 (t),109.0 (dꢃ2),109.8 (d),118.6 (s),122.3 (d),123.0 (s),124.4 (dꢃ2),
124.5 (d), 126.0 (s), 131.1 (s), 134.5 (s), 161.6 (s). Anal. Calcd for
C18H19N3O: C, 73.69; H, 6.53; N,14.32. Found: C, 73.89; H, 6.41; N,14.25.
IR: 3230 (NH), 1597 (CO) cmꢀ1. 1H NMR (CDCl3):
d
1.63 (t, J¼6.8 Hz,
2H, CH2),1.82 (q, J¼6.8 Hz, 2H, CH2), 2.60 (q, J¼6.8 Hz, 2H, CH2), 3.66
(t, J¼6.8 Hz, 2H, CH2), 6.34 (d, J¼2.0 Hz, 2H, 2ꢃCH), 6.95 (d, J¼2.0 Hz,
2H, 2ꢃCH), 7.14 (t, J¼7.9 Hz,1H, CH), 7.27 (t, J¼7.9 Hz,1H, CH), 7.51 (d,
J¼7.9 Hz, 1H, CH), 7.66 (d, J¼7.9 Hz, 1H, CH), 10.33 (br s, 1H, NH). 13C
4.4.7. [6-Methyl-3-(1H-pyrrol-1-yl)-1H-indol-2-yl]-(pyrrolidin-1-yl)
methanone (10g). White solid from ethanol, mp 164e165 ꢂC, yield
NMR (CDCl3):
d
24.0 (t), 25.9 (t), 46.5 (t), 46.7 (t), 109.8 (dꢃ2), 112.3
88%. IR: 3436 (NH), 1596 (CO) cmꢀ1. 1H NMR (CDCl3):
d 1.59e1.88
(d),118.7 (s),119.0 (d),120.7 (d),121.8 (dꢃ2),122.9 (s),123.4 (s),124.7
(d),134.6 (s),162.1 (s). Anal. Calcd for C17H17N3O: C, 73.10; H, 6.13; N,
15.04. Found: C, 72.78; H, 6.22; N, 15.35.
(m, 4H, 2ꢃCH2), 2.46 (s, 3H, CH3), 2.58 (t, J¼6.8 Hz, 2H, CH2), 3.67 (t,
J¼6.8 Hz, 2H, CH2), 6.33 (d, J¼1.6 Hz, 2H, 2ꢃCH), 6.95 (d, J¼1.6 Hz,
2H, 2ꢃCH), 6.98 (d, J¼8.2 Hz, 1H, CH), 7.25 (s, 1H, CH), 7.53 (d,
J¼8.2 Hz, 1H, CH), 10.19 (br s, 1H, NH). 13C NMR (CDCl3):
d 21.9 (q),
4.4.2. [5,6-Dimethoxy-3-(1H-pyrrol-1-yl)-1H-indol-2-yl]-(pyrroli-
24.0 (t), 25.9 (t), 46.5 (t), 46.6 (t), 109.7 (dꢃ2), 111.9 (d), 118.7 (d),
118.8 (s), 120.9 (s), 121.8 (dꢃ2), 121.7 (d), 121.8 (s), 134.9 (s), 135.0
(s), 162.2 (s). Anal. Calcd for C18H19N3O: C, 73.69; H, 6.53; N, 14.32.
Found: C, 73.57; H, 6.48; N, 13.93.
din-1-yl)methanone (10b). White solid from ethanol, mp
219e220 ꢂC, yield 96%. IR: 3227 (NH), 1596 (CO) cmꢀ1 1H NMR
.
(CDCl3):
d
1.26 (q, J¼6.8 Hz, 2H, CH2),1.67 (q, J¼6.8 Hz, 2H, CH2), 2.58
(t, J¼6.8 Hz, 2H, CH2), 3.67 (t, J¼6.8 Hz, 2H, CH2), 3.88 (s, 3H, CH3),
3.93 (s, 3H, CH3), 6.35 (d, J¼2.1 Hz, 2H, 2ꢃCH), 6.94 (d, J¼2.1 Hz, 2H,
2ꢃCH), 6.97 (s, 1H, CH), 6.97 (s,1H, CH), 10.10 (br s,1H, NH). 13C NMR
4.5. General method for the synthesis of pyrrolizino[2,3-b]
indol-4(5H)-one (5aeg)
(CDCl3): d 24.0 (t), 26.0 (t), 46.5 (t), 46.6 (t), 56.1 (q), 56.2 (q), 94.4 (d),
99.3 (d), 109.8 (dꢃ2), 116.0 (s), 118.9 (s), 121.8 (dꢃ2), 122.0 (s), 129.4
(s), 146.3 (s), 149.5 (s), 162.1 (s). Anal. Calcd for C19H21N3O3: C, 67.24;
H, 6.24; N, 12.38. Found: C, 66.96; H, 6.17; N, 12.55.
A solution of the appropriate pyrrolidin-1-yl[3-(1H-pyrrol-1-
yl)-1H-indol-2-yl]methanone 10aeg (1 mmol), in phosphorus
oxychloride (2.5 mL), was stirred at 70 ꢂC for 3e7 h. After cooling,
the reaction mixture was concentrated to give the iminium salt as
black solid. This was shaken with diethyl ether and filtered. The
dark residue was slowly added to a 10% aqueous sodium hydroxide
solution (10 mL) and heated to reflux for 2e6 h. After cooling, the
resulting suspension was extracted with ethyl acetate and the
combined organic layers were washed with water and brine, dried,
and evaporated to give a dark red solid. This residue was purified by
silica gel chromatography, eluting by dichloromethane/ethyl ace-
tate (95:5), to afford pyrrolizinoindolones 5aeg.
4.4.3. [5-Chloro-3-(1H-pyrrol-1-yl)-1H-indol-2-yl]-(pyrrolidin-1-yl)
methanone (10c). White solid from ethanol, mp 252e253 ꢂC, yield
91%. IR: 3221 (NH), 1596 (CO) cmꢀ1 1H NMR (CDCl3):
. d 1.65 (q,
J¼6.6 Hz, 2H, CH2), 1.82 (q, J¼6.6 Hz, 2H, CH2), 2.58 (t, J¼6.6 Hz, 2H,
CH2), 3.65 (t, J¼6.6 Hz 2H, CH2), 6.35 (d, J¼1.6 Hz, 2H, 2ꢃCH), 6.91
(d, J¼1.6 Hz, 2H, 2ꢃCH), 7.22 (d, J¼8.7 Hz, 1H, CH), 7.43 (d, J¼8.7 Hz,
1H, CH), 7.62 (s, 1H, CH), 10.67 (br s, 1H, NH). 13C NMR (CDCl3):
d
24.0 (t), 25.9 (t), 46.6 (t), 46.7 (t), 110.2 (dꢃ2), 113.5 (d), 118.2 (s),
118.4 (d), 121.7 (dꢃ2), 123.9 (s), 124.7 (s), 125.3 (d), 126.5 (s), 132.9
(s), 161.7 (s). Anal. Calcd for C17H16ClN3O: C, 65.07; H, 5.14; N, 13.39.
Found: C, 64.79; H, 5.01; N, 13.58.
4.5.1. Pyrrolizino[2,3-b]indol-4(5H)-one (5a). Red solid from etha-
nol, mp 250e251 ꢂC, yield 92%. IR: 3180 (NH), 1655 (CO) cmꢀ1. 1H
NMR (DMSO-d6):
d
6.05 (dd, J¼3.7, 2.6 Hz,1H, CH), 6.58 (d, J¼3.7 Hz,
4.4.4. [4-Chloro-3-(1H-pyrrol-1-yl)-1H-indol-2-yl]-(pyrrolidin-1-yl)
1H, CH), 7.12 (t, J¼8.0 Hz, 1H, CH), 7.25 (t, J¼8.0 Hz, 1H, CH), 7.36 (d,
methanone (10d). White solid from ethanol, mp 191e192 ꢂC, yield
J¼8.0 Hz, 1H, CH), 7.50 (d, J¼2.6 Hz, 1H, CH), 7.84 (d, J¼8.0 Hz, 1H,
95%. IR: 3251 (NH), 1589 (CO) cmꢀ1
.
1H NMR (CDCl3):
d
1.66 (q,
CH), 11.82 (br s, 1H, NH). 13C NMR (DMSO-d6):
d 112.3 (d), 112.9 (s),
J¼6.9 Hz, 2H, CH2), 1.84 (q, J¼6.9 Hz, 2H, CH2), 2.62 (t, J¼6.9 Hz, 2H,
CH2), 3.65 (t, J¼6.9 Hz, 2H, CH2), 6.28 (t, J¼2.1 Hz, 2H, 2ꢃCH), 6.88 (t,
J¼2.1 Hz, 2H, 2ꢃCH), 7.10 (dd, J¼7.7, 1.3 Hz, 1H, CH), 7.18 (t, J¼7.7 Hz,
1H, CH), 7.42 (dd, J¼7.7, 1.3 Hz, 1H, CH), 11.07 (br s, 1H, NH). 13C NMR
114.1 (d), 114.6 (d), 119.1 (d), 121.2 (d), 123.2 (d), 125.8 (d), 128.6 (s),
133.6 (s), 134.2 (s), 140.6 (s), 172.0 (s). Anal. Calcd for C13H8N2O: C,
74.99; H, 3.87; N, 13.45; Found: C, 75.08; H, 4.11; N, 13.26.
(CDCl3):
d
23.9 (t), 26.0 (t), 46.8 (t), 47.0 (t), 108.9 (dꢃ2), 117.6 (s),
4.5.2. 7,8-Dimethoxypyrrolizino[2,3-b]indol-4(5H)-one
(5b). Red
120.3 (s), 111.1 (d), 121.9 (d), 124.5 (dꢃ2), 124.7 (d), 125.7 (s), 126.9
solid from ethanol, mp 277e278 ꢂC, yield 98%. IR: 3195 (NH), 1658

3378
P. Diana et al. / Tetrahedron 67 (2011) 3374e3379
(CO) cmꢀ1. 1H NMR (DMSO-d6):
d
3.82 (s, 6H, 2ꢃCH3), 6.01 (t, J¼3.4,
4.6.1. 5-Methylpyrrolizino[2,3-b]indol-4(5H)-one (6a). Red ꢀs1olid
from ethanol, mp 182e183 ꢂC, yield 75%. IR: 1668 (CO) cm 1H
.
2.8Hz,1H, CH), 6.48(d,J¼3.4 Hz,1H, CH), 6.74 (s,1H, CH), 7.30 (s,1H, CH),
7.50 (d, J¼2.8 Hz, 1H, CH), 11.49 (s, 1H, NH). 13C NMR (DMSO-d6):
d
55.5
NMR (DMSO-d6):
d
3.79 (s, 3H, CH3), 6.00 (dd, J¼3.6, 2.6 Hz,1H, CH),
(q), 55.8 (q), 95.3 (d), 99.4 (d),105.9 (s),111.8 (d),113.5 (d),122.6 (d),126.5
(s),134.2(s),135.0(s),136.7 (s),146.6(s),150.4 (s),170.9(s). Anal. Calcd for
C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C, 67.38; H, 4.17; N, 10.31.
6.55 (d, J¼3.6 Hz,1H, CH), 6.85 (d, J¼2.6 Hz,1H, CH), 7.11 (t, J¼8.1 Hz,
1H, CH), 7.22 (t, J¼8.1 Hz, 1H, CH), 7.28 (d, J¼8.1 Hz, 1H, CH), 7.47 (d,
J¼8.1 Hz,1H, CH). 13C NMR (DMSO-d6):
d 30.5 (q),111.4 (d),112.4 (d),
113.3 (s), 114.7 (d), 119.0 (d), 121.4 (d), 121.5 (d), 125.6 (d), 129.5 (s),
133.6 (s), 134.7 (s), 141.4 (s), 173.2 (s). Anal. Calcd for C14H10N2O: C,
75.66; H, 4.54; N, 12.60; Found: C, 75.38; H, 4.67; N, 12.74.
4.5.3. 8-Chloropyrrolizino[2,3-b]indol-4(5H)-one (5c). Red solid
from ethanol, mp 294e295 ꢂC, yield 96%. IR: 3170 (NH), 1685
(CO) cmꢀ1. 1H NMR (DMSO-d6):
d
6.06 (dd, J¼3.7, 2.6 Hz, 1H, CH),
6.61 (d, J¼3.7 Hz, 1H, CH), 7.22 (dd, J¼9.0, 1.7 Hz, 1H, CH), 7.37 (d,
J¼9.0 Hz, 1H, CH), 7.60 (d, J¼2.6 Hz, 1H, CH), 8.05 (d, J¼1.7 Hz, 1H,
4.6.2. 7,8-Dimethoxy-5-methylpyrrolizino[2,3-b]indol-4(5H)-one
(6b). Red solid from ethanol, mp 228e229 ꢂC, yield 84%. IR: 1658
CH), 12.08 (br s, 1H, NH). 13C NMR (DMSO-d6):
d
112.5 (d), 113.4 (s),
(CO) cmꢀ1. 1H NMR (CDCl3):
d 3.70 (s, 3H, CH3), 3.90 (s, 3H, CH3),
115.0 (d), 115.8 (d), 118.3 (d), 123.7 (d), 125.6 (d), 125.8 (s), 130.2 (s),
133.0 (s), 133.4 (s), 138.8 (s), 171.8 (s). Anal. Calcd for C13H7ClN2O: C,
64.34; H, 2.91; N, 11.54. Found: C, 64.65; H, 3.03; N, 11.85.
3.94 (s, 3H, CH3), 5.96 (t, J¼3.5, 2.3 Hz,1H, CH), 6.48 (d, J¼3.5 Hz,1H,
CH), 6.51 (s, 1H, CH), 6.68 (s, 1H, CH), 6.76 (d, J¼2.3 Hz, 1H, CH). 13C
NMR (CDCl3):
d 30.6 (q), 56.1 (q), 56.2 (q), 92.8 (d), 98.7 (d), 106.2
(s), 112.0 (d), 113.7 (d), 120.7 (d), 127.8 (s), 134.0 (s), 135.3 (s), 137.4
(s), 146.8 (s), 150.4 (s), 172.1 (s). Anal. Calcd for C16H14N2O3: C,
68.07; H, 5.00; N, 9.92. Found: C, 67.87; H, 5.32; N, 10.02.
4.5.4. 9-Chloropyrrolizino[2,3-b]indol-4(5H)-one (5d). Red solid
fromethanol, mp 290e291 ꢂC, yield88%. IR:3174 (NH),1673 (CO)cmꢀ1
.
1H NMR (DMSO-d6):
d
6.10 (t, J¼3.1 Hz, 1H, CH), 6.67 (d, J¼3.1 Hz, 1H,
CH), 7.20e7.39 (m, 4H, 4ꢃCH),12.32 (br s,1H, CH).13CNMR(DMSO-d6):
4.6.3. 8-Chloro-5-methylpyrrolizino[2,3-b]indol-4(5H)-one
(6c). Red solid from ethanol, mp 237e238 ꢂC, yield 83%. IR: 1671
d
112.6 (s), 112.8 (d), 113.3 (d), 115.4 (d), 121.0 (d), 122.9 (s), 124.4 (d),
126.2 (d),129.8 (s),132.4 (s),133.8 (s), 141.1 (s), 171.5 (s). Anal. Calcd for
C13H7ClN2O: C, 64.34; H, 2.91; N,11.54. Found: C, 64.10; H, 2.76; N,11.74.
(CO) cmꢀ1. 1H NMR (DMSO-d6):
d
3.78 (s, 3H, CH3), 6.06 (dd, J¼3.7,
2.5 Hz, 1H, CH), 6.63 (d, J¼3.7 Hz, 1H, CH), 7.27 (dd, J¼9.1, 2.1 Hz, 1H,
CH), 7.54 (d, J¼9.1 Hz, 1H, CH), 7.59 (d, J¼2.5 Hz, 1H, CH), 8.03 (d,
4.5.5. 7-Chloropyrrolizino[2,3-b]indol-4(5H)-one (5e). Red solid
from ethanol, mp 283e284 ꢂC, yield 94%. IR: 3163 (NH), 1670
J¼2.1 Hz,1H, CH). 13C NMR (DMSO-d6):
d 30.6 (q),112.6 (d),113.0 (s),
114.0 (d), 115.2 (d), 118.4 (d), 123.7 (d), 125.5 (d), 126.1 (s), 130.1 (s),
131.6 (s), 133.4 (s), 139.3 (s), 171.8 (s). Anal. Calcd for C14H9ClN2O: C,
65.51; H, 3.53; N, 10.91. Found: C, 65.36; H, 3.86; N, 11.03.
(CO) cmꢀ1. 1H NMR (DMSO-d6):
d
6.07 (dd, J¼3.4, 2.6 Hz, 1H, CH),
6.60 (d, J¼3.4 Hz, 1H, CH), 7.15 (dd, J¼8.7, 1.8 Hz, 1H, CH), 7.38 (d,
J¼1.8 Hz, 1H, CH), 7.54 (d, J¼2.6 Hz, 1H, CH), 7.90 (d, J¼8.7 Hz, 1H,
CH), 12.00 (br s, 1H, CH). 13C NMR (DMSO-d6):
d
111.6 (s), 112.5 (d),
4.6.4. 9-Chloro-5-methylpyrrolizino[2,3-b]indol-4(5H)-one
113.5 (d), 115.0 (d), 120.7 (d), 121.8 (d), 123.4 (d), 129.5 (s), 130.1 (s),
133.5 (s), 133.9 (s), 140.6 (s), 171.7 (s). Anal. Calcd for C13H7ClN2O: C,
64.34; H, 2.91; N, 11.54. Found: C, 64.40; H, 3.14; N, 11.19.
(6d). Red solid from ethanol, mp 239e240 ꢂC, yield 72%. IR: 1659
(CO) cmꢀ1. 1H NMR (CDCl3):
d
3.84 (s, 3H, CH3), 6.02 (d, J¼3.4 Hz,1H,
CH), 6.62 (d, J¼3.4 Hz, 1H, CH), 7.13e7.26 (m, 4H, 4ꢃCH). 13C NMR
(CDCl3):
d 30.8 (q), 109.9 (d), 112.4 (d), 113.4 (s), 115.7 (d), 121.3 (d),
4.5.6. 9-Methylpyrrolizino[2,3-b]indol-4(5H)-one (5f). Red solid
124.5 (d), 124.7 (s), 125.7 (d), 130.3 (s), 132.3 (s), 134.5 (s), 141.8 (s),
172.7 (s). Anal. Calcd for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91.
Found: C, 65.75; H, 3.19; N, 10.82.
from ethanol, mp 281e282 ꢂC, yield92%. IR:3210 (NH),1656 (CO)cmꢀ1
.
1H NMR (DMSO-d6):
d
2.62 (s, 3H, CH3), 6.07 (dd, J¼3.7, 2.6 Hz,1H, CH),
6.62 (d, J¼3.7 Hz, 1H, CH), 6.87e6.91 (m, 1H, CH), 7.12e7.19 (m, 3H,
3ꢃCH), 11.89 (br s, 1H, NH). 13C NMR (DMSO-d6):
d 21.1 (q), 111.6 (d),
4.6.5. 7-Chloro-5-methylpyrrolizino[2,3-b]indol-4(5H)-one
(6e). Red solid from ethanol, mp 174e175 ꢂC, yield 75%. IR: 1673
112.4 (d),114.0 (s),114.7 (d),121.6 (d),123.8 (d),126.0 (d),128.3 (s),128.9
(s), 134.2 (s), 134.6 (s), 140.7 (s), 171.8 (s). Anal. Calcd for C14H10N2O: C,
75.66; H, 4.54; N, 12.60. Found: C, 75.84; H, 4.41; N, 12.76.
(CO) cmꢀ1. 1H NMR (CDCl3):
d
3.78 (s, 3H, CH3), 6.02 (dd, J¼3.4, 2.0 Hz,
1H, CH), 6.57 (d, J¼3.4 Hz, 1H, CH), 6.83 (d, J¼2.0 Hz, 1H, CH), 7.08 (dd,
J¼8.7, 1.6 Hz, 1H, CH), 7.23 (d, J¼1.6 Hz, 1H, CH), 7.40 (d, J¼8.7 Hz, 1H,
CH). 13C NMR (CDCl3):
d 30.7 (q), 111.4 (d), 111.8 (s), 112.7 (d), 115.0 (d),
4.5.7. 3-Methylpyrrolizino[2,3-b]indol-4(5H)-one (5g). Red solid
from ethanol, mp 248e249 ꢂC, yield 90%. IR: 3176 (NH), 1662
119.8 (d),121.4 (d),122.5 (d),130.1 (s),131.6 (s),133.4 (s),134.6 (s),141.4
(s), 172.7 (s). Anal. Calcd for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91.
Found: C, 65.66; H, 3.20; N, 11.11.
(CO) cmꢀ1.1H NMR(DMSO-d6):
d
2.39 (s, 3H, CH3), 6.03 (t, J¼3.4, 2.7 Hz,
1H, CH), 6.55 (d, J¼3.4 Hz,1H, CH), 6.96 (d, J¼8.3 Hz,1H, CH), 7.12 (s,1H,
CH), 7.47 (d, J¼2.7 Hz,1H, CH), 7.72 (d, J¼8.3 Hz,1H, CH),11.67 (br s,1H,
NH). 13C NMR (DMSO-d6):
d 21.5 (q), 110.9 (s), 112.2 (d), 113.4 (d), 114.3
4.6.6. 5,9-Dimethylpyrrolizino[2,3-b]indol-4(5H)-one (6f). Red solid
from ethanol, mp 132e133 ꢂC, yield 80%. IR: 1671 (CO) cmꢀ1 1H
.
(d), 118.9 (d), 123.0 (d), 123.4 (d), 127.9 (s), 133.7 (s), 134.5 (s), 135.8 (s),
141.2 (s), 171.9 (s). Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N,12.60.
Found: C, 75.38; H, 4.67; N, 12.43.
NMR (CDCl3):
d
2.45 (s, 3H, CH3), 3.77 (s, 3H, CH3), 5.99 (dd, J¼3.4,
2.0 Hz, 1H, CH), 6.53 (d, J¼3.4 Hz, 1H, CH), 6.83 (d, J¼2.0 Hz, 1H, CH),
6.94 (d, J¼8.4 Hz, 1H, CH), 7.00 (s, 1H, CH), 7.36 (d, J¼8.4 Hz, 1H, CH).
13C NMR (CDCl3):
d 22.2 (q), 30.5 (q), 111.0 (d), 111.3 (s), 112.2 (d),
4.6. General method for the synthesis of 5-methylpyrrolizino
114.4 (d), 118.6 (d), 121.2 (d), 123.6 (d), 128.9 (s), 133.9 (s), 134.8 (s),
136.2 (s), 142.0 (s), 173.1 (s). Anal. Calcd for C15H12N2O: C, 76.25; H,
5.12; N, 11.86. Found: C, 76.38; H, 4.97; N, 12.14.
[2,3-b]indol-4(5H)-ones (6beg)
To a stirred solution of the appropriate indole-pyrrolizinone
5beg (1 mmol) in anhydrous toluene (10 mL), t-BuOK (1.36 mmol,
153 mg) and 1e2 drops of TDA-1 were added at 0 ꢂC. The reaction
mixture was kept at room temperature for 5e6 h, then iodo-
methane (1 mmol, 0.06 mL) was added dropwise and the reaction
mixture was stirred at room temperature for 18 h. The solvent was
removed under reduced pressure and the residue was debated into
water, filtered off, air dried, and recrystallized from diethyl ether to
afford N-methyl-pyrrolizinoindolones 6aeg.
4.6.7. 5,7-Dimethylpyrrolizino[2,3-b]indol-4(5H)-one (6g). Red solid
from ethanol, mp 173e174 ꢂC, yield 90%. IR: 1669 (CO) cmꢀ1.1H NMR
(CDCl3):
d
2.57 (s, 3H, CH3), 3.75 (s, 3H, CH3), 6.00 (dd, J¼3.5, 2.6 Hz,
1H, CH), 6.57 (d, J¼3.5 Hz,1H, CH), 6.84 (d, J¼2.6 Hz,1H, CH), 6.87 (d,
J¼8.4 Hz,1H, CH), 7.01 (d, J¼8.4 Hz,1H, CH), 7.17 (t, J¼8.4 Hz,1H, CH).
13C NMR (CDCl3):
d 21.4 (q), 30.5 (q), 108.8 (d), 111.5 (s), 112.2 (d),
114.4 (s), 114.8 (d), 121.8 (d), 122.6 (d), 125.9 (d), 129.4 (s), 134.1 (s),

P. Diana et al. / Tetrahedron 67 (2011) 3374e3379
3379
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135.2 (s), 141.5 (s), 173.1 (s). Anal. Calcd for C15H12N2O: C, 76.25; H,
5.12; N, 11.86. Found: C, 76.09; H, 5.23; N, 12.01.
Acknowledgements
This work was financially supported by Ministero dell’Istruzione
ꢀ
dell’Universita e della Ricerca. We thank the National Cancer In-
stitute (Bethesda, MD) for the antitumor tests.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.03.060. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
7. Romagnoli, R.; Baraldi, P. G.; Sarkar, T.; Carrion, M. D.; Lopez, C. C.; Cruz-
Lopez, O.; Preti, D.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Di Cristina, A.;
Zonta, N.; Balzarini, J.; Brancale, A.; Hsich, H.; Hamel, E. J. Med. Chem. 2008,
5, 1464e1468.
References and notes
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