Highly selective base-catalyzed ring closing Ugi-adducts from the reaction of 2-formylindole, 2-bromoacetic acid, amines and isocyanides

Article abstract of DOI:10.1007/s13738-014-0495-6

The intermediate products of the Ugi reaction between indole-2-carboxaldehyde, 2-bromoacetic acid, amines and isocyanides were treated with Cs₂CO₃ in DMF to form a series of novel cyclized 1,2-dihydropyrazino[1,2-a]indol-3(4H)-ones (indole -NH cyclization) as major and piperazin-2-ones (amide -NH cyclization) as minor products.

Full text of DOI:10.1007/s13738-014-0495-6

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0495-6
ORIgINAl PAPER
Highly selective base‑catalyzed ring closing Ugi‑adducts
from the reaction of 2‑formylindole, 2‑bromoacetic acid, amines
and isocyanides
Morteza Shiri · Zahra Bozorgpour‑Savadjani
Received: 11 February 2014 / Accepted: 24 June 2014
© Iranian Chemical Society 2014
Abstract The intermediate products of the Ugi reaction
between indole-2-carboxaldehyde, 2-bromoacetic acid,
amines and isocyanides were treated with Cs2CO3 in DMF
to form a series of novel cyclized 1,2-dihydropyrazino[1,2-
a]indol-3(4H)-ones (indole –NH cyclization) as major
and piperazin-2-ones (amide –NH cyclization) as minor
products.
N-arylation in good to high yields. Zhang et al. [17] demon-
strated that products from the condensation of 1H-indole-
2-carbaldehyde, 2-iodobenzoic acid, isocyanides and
amines, in a highly selective controlled manner gave three
distinct sets of indole-based heterocycles under different
reaction conditions. The same group in another innova-
tive design, selectively prepared 5,6-dihydroindolo[1,2-
a]quinoxalines
and
6,7-dihydroindolo[2,3-c]quinolo-
Keywords Multicomponent condensation reactions ·
Indole · Base-catalyzed cyclization · Pyrazino[1,2-
a]indolone
nes [18]. Ivachtchenko and his co-workers established a
method for the synthesis of 2,3-dihydropyrazino[1,2-a]
indole-1,4-diones starting with the condensation of indole-
2-carboxylic acids, ethyl pyruvate, isocyanides, and pri-
mary amines followed by cyclization [19].
Introduction
Van der Eycken’s group, prepared special Ugi-adducts
containing indole and an alkyne motif with subsequent
treatment with different gold derivatives to obtain a
series of novel spiroindolines [20], azepinoindoles [21],
indoloazocines [22], azepino- and azocino-[c,d]indolones
[23]. Indolyl-substituted piperazinediones have been pre-
pared starting from the Ugi reaction of N-protected tryp-
tophane, amino acid esters, aldehydes and isocyanides,
followed by deprotection and subsequent cyclization with
the aid of MW radiation [24]. Very recently, an efficient
approach to synthesize indole-fused diketopiperazines was
developed by Pandey et al. [25] in which the Ugi reac-
tion and the subsequent cyclization occurred in a one-pot
reaction.
Using 2-(3-chloro-2-formyl-1H-indol-1-yl) acetic acid,
amines and isocyanides in a Ugi three component conden-
sation reactions involving an intramolecular cyclization
strategy resulted in the preparation of indoloketopiperazine
derivatives in moderate to high yields [26].
In continuation of our study on indole chemistry [6, 14,
27–30] and with the purpose to get access to a set of novel
heterocyclic compounds with potential biological activity,
Multicomponent reaction (MCR) techniques not only
make the rapid construction of diverse and complex mol-
ecules possible, but also save time and costs, and reduce
waste, in alignment with the principles of green chemistry
[1–8]. A subtle change in the design of MCRs, followed
by an efficient post-MCR transformation, can improve
the diversity and complexity of organic compounds. In
this context, indole derivatives in MCRs [6] gained much
attention due to their different reactive sites, and the indole
core being one of the most valuable scaffolds in many
important natural and synthetic products [9–15]. Balalaie
et al. [16] established a strategy for the one-pot syntheses
of indolo[1,2-a]quinoxalinones from the Ugi reaction of
aldehydes, 2-iodoaniline, 2-indole carboxylic acid, and iso-
cyanides, followed by the copper-catalyzed intramolecular
M. Shiri (*) · Z. Bozorgpour-Savadjani
Department of Chemistry, Faculty of Science, Alzahra University,
1993893973 Vanak, Tehran, Iran
e-mail: mshiri@alzahra.ac.ir
1 3

J IRAN CHEM SOC
we used 2-formylindole as aldehyde and bromoacetic acid
as acid sources in the Ugi reaction, followed by cyclization
of the intermediate under basic conditions.
1.2 Pink–yellow powder, mp 222–224 °C. FT-IR (KBr):
1
νmax = 3,300, 3,006, 2,928, 1,650, 731 cm−1. H-NMR
(400 MHz, CDCl3): δ = 1.00 (m, 3H), 1.24 (m, 2H), 1.57 (m,
3H), 1.86 (m, 2H), 3.63 (q, 2H), 3.75 (m, 1H), 5.36 (s, 1H),
5.68 (d, J = 8.04 Hz, 1H), 6.40 (d, J = 1.2 Hz, 1H), 7.05 (m,
1H), 7.16 (m, 2H), 7.28 (m, 5H), 7.54 (d, J = 7.84 Hz, 1H),
9.47 (s, br, 1H) ppm. CHN calculated for C24H26BrN3O2: C,
61.54; H, 5.60; N, 8.97, Found C, 61.02; H, 5.42; N, 8.45.
1.4 White powder, mp 195–197 °C. FT-IR (KBr):
Experimental section
general
1
Chemicals were purchased from Fluka, Merck and Aldrich
chemical companies. Melting points are uncorrected. IR
spectra were recorded on a Shimadzu infra red spectros-
copy IR-435. Nuclear magnetic resonance (NMR) spectra
were recorded on a Bruker Avance 400 MHz Spectrometer
in CDCl3 as solvent. A leco CHNS, model 932 was used
for elemental analysis.
νmax = 3,305, 3,074, 2,928, 1,554, 720 cm−1. H-NMR
(400 MHz, CDCl3): δ = 1.03 (m, 3H), 1.27 (m, 2H), 1.60
(m, 5H), 3.63 (m, 2H), 3.71 (s, 4H), 5.40 (s, 1H), 5.72
(d, J = 8 Hz, 1H), 6.40 (d, J = 1.12 Hz, 1H), 6.76 (d,
J = 8.88 Hz, 2H), 7.12 (m, 5H), 7.28 (d, J = 8.24 Hz, 1H),
7.51 (d, J = 7.88 Hz, 1H), 9.49 (s, br, 1H) ppm. 13C-NMR
(100 MHz, CDCl3): δ = 24.7, 24.8, 25.3, 27.6, 32.7, 32.8,
49.0, 55.5, 63.0, 105.3, 111.7, 114.9, 120.0, 120.6, 122.8,
127.1, 129.4, 131.5, 133.8, 136.6, 159.9, 166.3, 168.2 ppm.
CHN calculated for C25H28BrN3O3: C, 60.24; H, 5.66; N,
8.43, Found C, 60.33; H, 5.51; N, 8.08.
The synthesis of Ugi-adduct
To a stirred solution of 2-formylindole (1 mmol) and amine
(1 mmol) in MeOH (5 ml), were added, bromoacetic acid
(1 mmol) and then isocyanide (1 mmol) at room tempera-
ture. The reaction process was monitored by TlC. After
24 h, the solvent was evaporated under reduced pressure
and the residue was purified by column chromatography
using petroleum ether-EtOAc as eluent.
1.5 White powder, mp 130–133 °C. FT-IR (KBr):
1
νmax = 3,264, 3,082, 2,975, 1,639, 1,562, 725 cm−1. H-
NMR (400 MHz, CDCl3): δ = 1.26 (s, 9H), 2.67 (s, 3H),
3.64 (q, 2H), 5.41 (s, 1H), 5.78 (s, 1H), 6.39 (s, 1H), 7.03
(t, J = 6.36 Hz, 5H), 7.11 (m, 1H), 7.25 (d, J = 8.12 Hz,
1H), 7.51 (d, J = 7.92 Hz, 1H), 9.42 (s, br, 1H) ppm. 13C-
NMR (100 MHz, CDCl3): δ = 18.4, 21.1, 28.6, 51.8, 55.4,
105.1, 111.6, 119.9, 120.6, 122.7, 127.1, 128.0, 130.3,
131.7, 136.6, 138.3, 139.3, 166.5, 167.9 ppm. CHN calcu-
lated for C23H26BrN3O2: C, 60.53; H, 5.74; N, 9.21, Found
C, 60.65; H, 5.84; N, 9.32.
general procedure for the cyclization of Ugi-adducts
To a solution of Ugi-adduct (0.5 mmol) in DMF (10 ml)
was added Cs2CO3 (1 equiv.) at room temperature. The
reaction process was monitored by TlC. After 30 min, the
solvent was evaporated under reduced pressure and the res-
idue was purified by column chromatography using petro-
leum ether-EtOAc as eluent.
1.6 White powder, mp 169–171 °C. FT-IR (KBr):
νmax = 3,303, 3,300, 3,074, 2,933, 1,645, 1,559, 698 cm−1
.
1H-NMR (400 MHz, CDCl3): δ = 0.98 (m, 3H), 1.23
(m, 2H), 1.53 (m, 3H), 1.71 (m, 1H), 1.82 (m, 1H), 3.96
(m, 1H), 3.82 (s, 2H), 4.62 (d, J = 3.32 Hz, 2H), 5.14
(s, 1H), 5.60 (d, J = 7.92 Hz, 1H), 6.28 (s, 1H), 7.05
(d, J = 7.88 Hz, 1H), 7.16 (m, 6H), 7.24 (m, 1H), 7.48
(d, J = 7.84 Hz, 1H), 9.54 (s, br, 1H) ppm. 13C-NMR
(100 MHz, CDCl3): 24.7, 24.8, 25.3, 26.7, 32.6, 32.8, 48.8,
53.1, 59.9, 105.5, 111.7, 120.0, 120.6, 122.9, 126.9, 127.1,
128.0, 128.9, 131,6, 135.2, 136.6, 166.2, 169.1, ppm. CHN
calculated for C25H28BrN3O2: C, 62.24; H, 5.85; N, 8.71,
Found C, 62.42; H, 5.54; N, 8.65.
Physical and spectral data
1.1 White powder, mp 230–232 °C. FT-IR (KBr):
νmax = 3,323, 3,287, 3,082, 2,927, 1,653, 1,561, 712 cm−1
.
1H-NMR (400 MHz, CDCl3): δ = 1.00 (m, 3H), 1.25
(m, 2H), 1.57 (m, 3H), 1.79 (m, 2H), 2.27 (s, 3H), 3.59
(d, J = 11.76 Hz, 2H), 3.73 (m, 1H), 5.33 (s, 1H), 5.66
(d, J = 7.96 Hz, 1H), 6.40 (d, J = 0.96 Hz, 1H), 7.06
(t, J = 6.56 Hz, 4H), 7.15 (t, J = 7.9 Hz, 2H), 7.28 (d,
J = 8.04 Hz, 1H), 7.51 (d, J = 7.88 Hz, 1H), 9.49 (s, br,
1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 1.1, 24.7,
24.8, 25.3, 27.6, 32.7, 32.8, 49.0, 63.4, 77.2, 105.3, 111.7,
120.0, 120.6, 122.8, 127.1, 127.9, 130.4, 131.6, 136.6,
138.8, 139.3, 166.2, 168.1 ppm. CHN calculated for
C25H28BrN3O2: C, 62.24; H, 5.85; N, 8.71, Found C, 62.18;
H, 5.91; N, 8.66.
2.1a Yellow powder, mp 239–241 °C. FT-IR (KBr):
1
νmax = 3,315, 3,063, 2,924, 1,669, 1,546 cm−1. H-NMR
(400 MHz, CDCl3): δ = 1.07 (m, 3H), 1.33 (m, 2H), 1.61
(m, 3H), 1.82 (m, 1H), 1.92 (m, 1H), 2.28 (s, 3H), 3.58 (m,
1H), 4.93 (q, 2H), 5.22 (s, 1H), 5.58 (d, J = 7.4 Hz, 1H),
6.38 (s, 1H), 7.09–7.23 (m, 7H), 7.54 (d, J = 7.88 Hz,
1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 21.1, 22.6,
24.6, 24.7, 25.3, 29.7, 32.5, 32.8, 47.1, 49.2, 63.5, 97.53,
1 3

J IRAN CHEM SOC
109.1, 120.6, 120.9, 122.4, 126.7, 128.2, 129.1, 130.2,
135.7, 138.1, 138.3, 166.2, 167.1 ppm. CHN calculated for
C25H27N3O2: C, 74.79; H, 6.78; N, 10.47, Found C, 74.77;
H, 6.50; N, 10.32.
J = 4.47 Hz, 3H), 7.51 (d, J = 8.16 Hz, 1H), 7.60 (d,
J = 7.92 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H) ppm. 13C-
NMR (100 MHz, CDCl3): δ = 18.4, 24.0, 24.1, 24.9,
31.6, 32.1, 46.6, 47.4, 48.0, 55.3, 61.8, 96.7, 109.7, 114.3,
120.0, 120.3, 121.3, 127.7, 127.9, 130.2, 133.7, 134.9,
158.2, 165.7, 167.5 ppm. CHN calculated for C25H27N3O3:
C, 71.92; H, 6.52; N, 10.06, Found C, 72.11; H, 6.68; N,
10.19.
2.1b Red powder, 79–81 °C. FT-IR (KBr): νmax = 3,313,
3,003, 2,924, 1,655, 1,452 cm−1 1H-NMR (400 MHz,
.
CDCl3): δ = 0.78 (m, 3H), 1.00 (m, 2H), 1.42 (m, 2H), 1.62
(m, 2H), 1.78 (m, 1H), 2.24 (s, 3H), 3.94 (q, 2H), 4.23 (m,
1H), 5.50 (s, 1H), 6.5 (s, 1H), 7.09 (m, 4H), 7.24 (m, 2H),
7.51 (d, J = 7.84 Hz, 1H), 8.61 (s, br, 1H) ppm. 13C-NMR
(100 MHz, CDCl3): δ = 21.0, 22.7, 25.1, 25.3, 25.4, 29.4,
29.6, 29.7, 45.47, 53.1, 63.5, 100.9, 111.2, 120.3, 120.6,
122.7, 124.8, 127.7, 129.8, 131.5, 136.9, 137.4, 164.5,
165.2 ppm. CHN calculated for C25H27N3O2: C, 74.79; H,
6.78; N, 10.47, Found C, 74.61; H, 6.84; N, 10.55.
2.4b White powder, mp 222–224 °C. FT-IR (KBr):
1
νmax = 3,268, 3,044, 2,923, 1,661, 1,623 cm−1. H-NMR
(600 MHz, DMSO): δ = 1.22 (m, 5H), 1.64 (m, 5H), 3.70
(s, 3H), 4.11 (m, 2H), 4.38 (d, J = 17.28 Hz, 1H), 5.47
(s, 1H), 6.45 (s, 1H), 6.86 (d, J = 8. 94 Hz, 1H), 6.97 (m,
1H), 7.07 (m, 1H), 7.16 (d, J = 8.88 Hz, 2H), 7.35 (d,
J = 8.16 Hz, 1H), 7.47 (d, J = 7.86 Hz, 1H), 11.21 (s, br,
1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 25.2, 25.6,
28.7, 29.1, 45.5, 48.0, 48.1, 48.3, 53.0, 55.6, 63.0, 100.8,
111.9, 114.5, 119.6, 120.5, 121.9, 128.0, 128.4, 132.5,
134.5, 136.8, 158.5, 163.0, 164.3 ppm. CHN calculated for
C25H27N3O3: C, 71.92; H, 6.52; N, 10.06, Found C, 71.35;
H, 6.42; N, 10.15.
2.2a Orange powder, mp 229–231 °C. FT-IR (KBr):
1
νmax = 3,322, 3,061, 2,958, 1,662, 1,594 cm−1. H-NMR
(400 MHz, CDCl3): δ = 0.79 (m, 1H), 1.00 (m, 4H), 1.21
(m, 2H), 1.58 (m, 3H), 1.78 (m, 1H), 3.59 (m, 1H), 4.94 (q,
2H), 5.24 (s, 1H), 5.57 (d, J = 7.72 Hz, 1H), 6.39 (s, 1H),
7.10–7.35 (m, 8H), 7.54 (m, 1H) ppm. CHN calculated for
C24H25N3O2: C, 74.39; H, 6.50; N, 10.84, Found C, 74.12;
H, 6.42; N, 10.55.
2.5a Orange powder, mp 262–264 °C. FT-IR (KBr):
1
νmax = 3,295, 3,008, 2,924, 1,691, 1,649, 745 cm−1. H-
2.2b Purple powder, mp 82–84 °C. FT-IR (KBr):
NMR (400 MHz, CDCl3): δ = 1.19 (d, J = 2.52 Hz, 9H),
2.29 (s, 3H), 4.93 (m, 2H), 5.14 (d, J = 4.24 Hz, 1H), 5.44
(s, 1H), 6.37 (d, J = 2.96 Hz, 1H), 7.13 (m, 7H), 7.55 (d,
J = 7.92 Hz, 1H) ppm. 13C-NMR (100 MHz, CDCl3):
δ = 21.1, 28.4, 47.1, 52.2, 64.1, 97.3, 109.1, 120.6, 120.9,
122.3, 126.8, 128.2, 129.2, 130.2, 135.7, 138.1, 138.3,
166.1, 167.2 ppm.
1
νmax = 3,301, 3,057, 2,957, 1,655, 1,546 cm−1. H-NMR
(400 MHz, CDCl3): δ = 1.10 (m, 3H), 1.32 (m, 2H), 1.61
(m, 4H), 1.89 (m, 2H), 3.94 (q, 2H), 4.23 (m, 1H), 5.54
(s, 1H), 6.51 (s, 1H), 7.05 (m, 1H), 7.16 (m, 2H), 7.26-
7.37 (m, 5H), 7.50 (d, J = 7.8 Hz, 1H), 8.66 (s, br, 1H)
ppm. 13C-NMR (100 MHz, CDCl3): δ = 21.6, 24.1, 24.3,
24.3, 28.4, 28.5, 28.6, 30.9, 44.4, 52.1, 62.41, 75.6, 99.9,
110.2, 119.3, 119.6, 121.7, 123.8, 126.3, 126.6, 128.2,
130.3, 135.9, 138.4, 163.4, 164.1 ppm. CHN calculated for
C24H25N3O2: C, 74.39; H, 6.50; N, 10.84, Found C, 74.45;
H, 6.65; N, 10.09.
CHN calculated for C23H25N3O2: C, 73.57; H, 6.71; N,
11.19, Found C, 73.42; H, 6.54; N, 11.52.
2.6a Yellow powder, mp 29–32 °C. FT-IR (KBr):
νmax = 3,300, 3,008, 2,925, 1,705, 1,660, 1,463 cm−1
.
1H-NMR (400 MHz, CDCl3): δ = 1.03 (m, 3H), 1.14 (m,
2 Hz), 1.34 (m, 3H), 1.63 (m, 1H), 1.90 (m, 1H), 3.54 (m,
1H), 4.08 (d, J = 15.16 Hz, 1H), 4.87 (m, 3H), 5.44 (m,
2H), 6.27 (s, 1H), 7.03 (m, 2H), 7.23 (m, 6H), 7.49 (d,
J = 7.84 Hz, 1H) ppm. CHN calculated for C25H27N3O2:
C, 74.79; H, 6.78; N, 10.47, Found C, 74.65; H, 6.47; N,
10.35.
2.3a White powder, mp 241–243 °C. FT-IR (KBr):
1
νmax = 3,301, 3,053, 2,924, 1,681, 1,646 cm−1. H-NMR
(400 MHz, CDCl3): δ = 0.77 (m, 3H), 0.96 (m, 3H), 1.20
(m, 4H), 1.67 (m, 1H), 2.03 (s, 3H), 2.28 (s, 1H), 3.60 (m,
1H), 5.11 (m, 3H), 5.54 (d, J = 7.96 Hz, 1H), 6.38 (s, 1H),
7.01 (m, 1H), 7.18–7.27 (m, 7H), 7.55 (d, J = 7.92 Hz,
1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 17.5, 24.5,
24.6, 25.3, 32.6, 32.9, 47.2, 49.2, 62.8, 97.3, 109.1, 120.6,
120.9, 122.4, 127.2, 128.1, 128.3, 128.7, 129.2, 131.2,
135.2, 135.8, 139.6, 165.9, 167.1 ppm. CHN calculated for
C25H27N3O2: C, 74.79; H, 6.78; N, 10.47, Found C, 74.65;
H, 6.58; N, 10.36.
2.6b White powder, mp 29–32 °C. FT-IR (KBr):
νmax = 3,281, 3,085, 2,928, 1,653 cm−1
.
1H-NMR
(400 MHz, CDCl3): δ = 0.86 (m, 3H), 1.05 (m, 1H), 1.27
(m, 1H), 1.52 (m, 3H), 1.64 (m, 2H), 3.80 (m, 1H), 3.92
(m, 2H), 4.16 (m, 2H), 5.03 (s, 1H), 5.54 (d, J = 14.8 Hz,
1H), 6.31 (s, 1H), 7.59 (m, 2H), 7.15 (m, 2H), 7.26 (m,
5H), 8.42 (s, br, 1H) ppm. CHN calculated for C25H27N3O2:
C, 74.79; H, 6.78; N, 10.47, Found C, 74.97; H, 6.64; N,
10.55.
2.4a White powder, mp 255–257 °C. FT-IR (KBr):
1
νmax = 3,293, 3,087, 2,925, 1,737, 1,656 cm−1. H-NMR
(600 MHz, DMSO): δ = 1.09 (m, 6H), 1.59 (m, 5H),
3.45 (m, 1H), 3.79 (s, 3H), 4.91 (d, J = 16.98 Hz, 1H),
5.07 (d, J = 17.16 Hz, 1H), 5.59 (s, 1H), 6.5 (s, 1H), 7.01
(d, J = 8.76 Hz, 2H), 7.11 (d, J = 7.5 Hz, 1H), 7.17 (t,
3a White powder, mp 234–236 °C. FT-IR (KBr):
1
νmax = 3,264, 3,083, 2,931, 1,654, 1,561 cm−1. H-NMR
(400 MHz, CDCl3): δ = 1.06 (m, 3H), 1.33 (m, 2H), 1.67
1 3

J IRAN CHEM SOC
(m, 3H), 1.89 (m, 1H), 1.95 (m, 1H), 2.30 (s, 3H), 3.64
(d, J = 0.6 Hz, 2H), 3.81 (m, 1H), 5.65 (d, J = 7.76 Hz,
1H), 5.92 (s, 1H), 7.08 (d, J = 8.48 Hz, 4H), 7.17 (d,
J = 8.48 Hz, 2H), 7.26 (m, 2H) ppm. 13C-NMR (100 MHz,
CDCl3): δ = 21.1, 24.7, 24.8, 32.7, 32.84, 48.8, 64.8,
128.6, 129.8, 129.9, 131.7, 132.6, 134.7, 136.1, 139.1,
167.3, 167.6 ppm. CHN calculated for C23H26BrClN2O2:
C, 57.81; H, 5.48; N, 5.86, Found C, 57.77; H, 5.39; N,
5.81.
(d, J = 8.72 Hz, 2H), 7.01 (d, J = 8.64 Hz, 2H), 7.28 (s,
4H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 24.7, 24.8,
25.4, 27.4, 32.8, 48.8, 55.2, 64.5, 77.2, 114.0, 122.9, 125.6,
131.6, 132.2, 137.9, 159.8, 166.7, 168.1 ppm. CHN calcu-
lated for C23H26Br2N2O3: C, 51.32; H, 4.87; N, 5.20, Found
C, 51.39; H, 5.12; N, 5.02.
3g White powder, mp 223–225 °C. FT-IR (KBr):
1
νmax = 3,269, 3,067, 2,934, 1,653, 1,552, 712 cm−1. H-
NMR (400 MHz, CDCl3): δ = 1.12 (m, 3H), 1.34 (m, 2H),
1.64 (m, 3H), 1.95 (m, 3H), 2.14 (m, 2H), 3.60 (m, 2H),
3.77 (m, 4H), 5.65 (d, J = 7.88 Hz, 1H), 5.86 (s, 1H), 6.67
(d, J = 8.6 Hz, 1H), 6.82 (m, 1H), 7.03 (m, 2H), 7.22 (m,
3H), 7.63 (m, 1H) ppm. 13C-NMR (100 MHz, CDCl3):
δ = 17.7, 18.7, 24.7, 24.8, 25.4, 27.7, 28.1, 32.7, 32.8,
48.6, 48.7, 55.1, 55.2, 65.3, 113.5, 113.9, 125.0, 126.9,
127.2, 128.9, 129.2, 130.0, 130.6, 130.9, 131.3, 131.5,
132.0, 136.7, 137.2, 137.8, 159.7, 167.1, 167.7, 168.3 ppm.
CHN calculated for C24H29BrN2O3: C, 60.89; H, 6.17; N,
5.92, Found C, 60.65; H, 6.14; N, 5.87.
3b White powder, mp 229–231 °C. FT-IR (KBr):
νmax = 3,253, 3,085, 2,930, 1,672, 1,565, 712 cm−1
.
13C-
NMR (100 MHz, DMSO): δ = 24.3, 24.5, 25.0, 29.2,
32.0, 47.9, 60.5, 62.5, 63.0, 121.1, 121.4, 127.9, 128.0,
131.4, 131.8, 132.4, 132.6, 132.9, 133.7, 133.8, 137.1,
137.8, 165.3, 167.6, 168.1, 171.2 ppm. CHN calculated for
C22H23Br2ClN2O2: C, 48.69; H, 4.27; N, 5.16, Found C,
48.75; H, 4.31; N, 5.22.
3c White powder, mp 255–257 °C. FT-IR (KBr):
1
νmax = 3,327, 3,080, 2,913, 1,661, 1,557, 700 cm−1. H-
NMR (400 MHz, CDCl3): δ = 1.06 (m, 3H), 1.34 (m, 2H),
1.87 (m, 5H), 3.65 (t, J = 12.02 Hz, 2H), 3.81 (m, 1H),
5.65 (d, J = 7.8 Hz, 1H), 5.94 (s, 1H), 7.06–7.26 (m, 8H)
ppm. 13C-NMR (100 MHz, CDCl3): δ = 24.7, 24.8, 25.4,
27.59, 32.7, 32.8, 48.9, 64.8, 77.2, 128.6, 129.0, 129.2,
130.1, 131.7, 132.4, 134.7, 138.7, 167.1, 167.6 ppm. CHN
calculated for C22H23Br2ClN2O2: C, 56.97; H, 5.22; N,
6.04, Found C, 56.88; H, 5.31; N, 6.14.
3h White powder, mp 213–215 °C. FT-IR (KBr):
1
νmax = 3,269, 3,014, 2,938, 1,662, 1,562, 720 cm−1. H-
NMR (400 MHz, CDCl3): δ = 1.11 (m, 3H), 1.33 (m,
2H), 1.92 (m, 5H), 3.65 (q, 2H), 3.79 (m, 7H), 5.52 (d,
J = 7.92 Hz, 1H), 5.97 (s, 1H), 6.71 (d, J = 9 Hz, 5H),
7.01 (d, J = 8.64 Hz, 2H), 7.26 (m, 1H) ppm. 13C-NMR
(100 MHz, CDCl3): δ = 24.7, 24.8, 25.4, 27.9, 32.8, 32.9,
48.7, 55.2, 55.3, 64.7, 77.2, 113.7, 114.0, 126.1, 131.4,
131.5, 131.7, 159.4, 159.6, 167.3, 168.3 ppm. CHN calcu-
lated for C24H29BrN2O4: C, 58.90; H, 5.97; N, 5.72, Found
C, 58.78; H, 6.15; N, 5.63.
3d White powder, mp 239–241 °C. FT-IR (KBr):
1
νmax = 3,275, 3,078, 2,930, 1,655, 1,556, 737 cm−1. H-
NMR (400 MHz, CDCl3): δ = 1.15 (m, 5H), 1.33 (m, 2H),
1.57–1.97 (m, 9H), 2.16 (s, 1H), 3.60 (m, 2H), 3.79 (m,
1H), 5.78 (m, 1H), 5.85 (s, 1H), 7.08 (m, 3H), 7.23 (m,
4H), 7.57 (m, 1H) ppm. 13C-NMR (100 MHz, CDCl3):
δ = 17.7, 24.6, 24.7, 25.4, 27.4, 32.7, 32.8, 48.8, 65.1,
127.2, 128.3, 129.5, 130.5, 131.1, 131.4, 131.5, 132.0,
134.9, 137.0, 137.4, 167.4, 167.7 ppm. CHN calculated
for C23H26BrClN2O2: C, 57.81; H, 5.48; N, 5.86, Found C,
57.81; H, 5.42; N, 5.79.
3i White powder, mp 242–244 °C. FT-IR (KBr):
1
νmax = 3,266, 3,076, 2,927, 1,653, 1,557, 741 cm−1. H-
NMR (400 MHz, CDCl3): δ = 1.04 (m, 3H), 1.26 (m, 2H),
1.55 (m, 3H), 1.79 (m, 2H), 2.21 (s, 6H), 3.57 (q, 2H),
3.74 (m, 1H), 5.45 (d, J = 7.88 Hz, 1H), 5.83 (s, 1H), 6.93
(s, 7H), 7.19 (s, 1H) ppm. 13C-NMR (100 MHz, CDCl3):
δ = 21.1, 21.2, 24.7, 24.8, 25.4, 27.9, 32.7, 32.8, 48.7,
65.6, 77.2, 129.15, 129.6, 129.8, 130.2, 131.2, 136.65,
138.4, 138.6, 167.0, 168.2 ppm. CHN calculated for
C24H29BrN2O2: C, 63.02; H, 6.39; N, 6.12, Found C, 63.15;
H, 6.55; N, 6.27.
3e White powder, mp 215–217 °C. FT-IR (KBr):
1
νmax = 3,268, 3,080, 2,929, 1,659, 1,560, 714 cm−1. H-
NMR (400 MHz, CDCl3): δ = 1.14 (m, 3H), 1.34 (m, 2H),
1.86 (m, 5H), 2.31(s, 3H), 3.63 (q, 2H), 3.82 (m, 4H), 5.55
(d, J = 7.92 Hz, 1H), 5.94 (s, 1H), 6.72 (m, 2H), 7.04 (m,
4H), 7.27 (m, 2H) ppm. 13C-NMR (100 MHz, CDCl3):
δ = 21.1, 24.7, 24.8, 25.4, 27.9, 32.8, 32.9, 48.7, 55.2, 65.0,
77.2, 113.7, 126.1, 129.6, 129.9, 131.7, 136.4, 138.6, 159.6,
167.0, 168.3 ppm. CHN calculated for C24H29BrN2O3: C,
60.89; H, 6.17; N, 5.92, Found C, 60.72; H, 6.14; N, 6.15.
3f White powder, mp 214–216 °C. FT-IR (KBr):
3j White powder, mp 235–237 °C. FT-IR (KBr): 3,265,
3,077, 2,926, 1,658, 1,557, 715 cm−1. 1H-NMR (400 MHz,
CDCl3): δ = 1.03 (m, 3H), 1.37 (m, 5H), 1.85 (m, 1H), 1.95
(m, 1H), 2.30 (s, 3H), 3.63 (m, 2H), 3.81 (m, 1H), 5.42 (d,
J = 7.88 Hz, 1H), 5.99 (s, 1H), 7.01 (m, 4H), 7.31 (m, 3H)
ppm. 13C-NMR (100 MHz, CDCl3): δ = 21.1, 24.7, 24.8,
25.4, 27.4, 32.7, 32.8, 48.9, 65.0, 77.2, 122.8, 129.4, 130.2,
130.6, 132.1, 138.0, 138.8, 166.7, 168.0 ppm. CHN calcu-
lated for C23H26Br2N2O2: C, 52.89; H, 5.02; N, 5.36, Found
C, 52.95; H, 5.14; N, 5.51.
1
νmax = 3,263, 3,080, 2,929, 1,651, 1,562, 714 cm−1. H-
NMR (400 MHz, CDCl3): δ = 1.0 (m, 3H), 1.34 (m, 2H),
1.62 (m, 3H), 1.85 (m, 1H), 1.95 (m, 1H), 3.63 (q, 2H),
3.81 (m, 4H), 5.43 (d, J = 8.12 Hz, 1H), 6.00 (s, 1H), 6.73
3k White powder, mp 242–244 °C. FT-IR (KBr):
νmax = 3,270, 3,079, 2,929, 1,656, 1,558, 703 cm−1
.
1 3

J IRAN CHEM SOC
O
NH
N
N
O
CHO
2O
1
N
H
4
NH
2.1a, 73%
Cs2CO3
3
MeOH
BrCH2CO2H
CyHexNC
p-MeC6H4NH2
N
24 h, rt
95%
N
DMF, rt
30 min
5H
+
O
b
a
O
N
Br
1.1
N
N
H
O
2.1b, 16%
Scheme 1 Ugi reaction and selective cyclization of 1.1 to 2.1a and 2.1b
1H-NMR (400 MHz, CDCl3): δ = 0.94 (m, 3H), 1.05
(m, 2H), 1.53 (m, 5H), 2.19 (s, 3H), 3.58 (m, 2H), 3.75
(m, 1H), 5.45(d, J = 7.76 Hz, 1H), 5.86 (s, 1H), 6.92 (s,
4H), 7.12 (m, 5H) ppm. 13C-NMR (100 MHz, CDCl3):
δ = 21.1, 24.7, 24.8, 25.4, 27.8, 32.7, 32.8, 48.8, 65.66,
77.2, 128.6, 129.0, 129.1, 130.2, 130.3, 130.3, 130.9,
138.5, 139.2, 166.9, 168.1, 168.2 ppm. CHN calculated for
C23H27BrN2O2: C, 62.31; H, 6.14; N, 6.32, Found C, 62.23;
H, 6.16; N, 6.27.
To evaluate the scope and limitations of the reaction,
different Ugi-adducts were synthesized in good to excel-
lent yields, followed by the subsequent cyclization reaction
(See Scheme 1 and Table 1). Using aniline as alternative
amine gave the diamide intermediate 1.2 and final product
2.2a in 82 % and compound 2.2b in 16 % yield (Table 1,
entry 1). The o-toluidine derivative 1.3 gave pyrazino[1,2-
a]indolone 2.3a in 55 % yield with trace amounts of 2.3b,
but the para-anisidine derivative 1.4 yielded both products
2.4a and 2.4b, respectively, in 59 and 10 % yield in the
presence of cesium carbonate (Table 1, entries 2 and 3). It
is interesting to note that 1.3 and 2.3a are isolated as a mix-
ture of diastereomers, due to the restricted rotation of the
ortho-methyl benzene group. The fact that 2.3a is obtained
as a 83:17 mixture of diastereomers suggests that one of
the diastereomers (major product) is most possibly both
the kinetically as well as thermodynamically determined
product.
Ugi product 1.5 containing tert-butyl as a bulky group
gave only 62 % corresponding cyclic product 2.5a (Table 1,
entry 4). Benzylamine, as a candidate for alkyl amines,
adequately followed the same trend both in terms of the
Ugi reaction and subsequent cyclization (Table 1, entry 5).
The apparent reason for the difference in the yields for
2.1a and 2.1b (and the corresponding reactions in Table 1)
is the stronger acid character of the indole N–H proton
(cyclization route a) in comparison to the amide N–H pro-
ton (cyclization route b).
Results and discussion
In the first step, the reaction of indole-2-carboxaldehyde,
2-bromoacetic acid, 4-methylaniline and cyclohexyl iso-
cyanide was set up (Scheme 1). The Ugi-adduct 1.1 was
isolated in 88 % yield. This is quite exceptional since it
has five nucleophilic positions which can potentially per-
form an intramolecular attack on the electrophilic –CH2-
Br group (numbered 1–5 in Scheme 1). In the second step,
treatment of compound 1.1 with Cs2CO3 in DMF (the
reaction is completed at room temperature during 30 min),
afforded 1,2-dihydropyrazino[1,2-a]indol-3(4H)-one 2.1a
in 73 % and piperazin-2-one 2.1b in 16 % yield. It should
be noted one-pot strategy gave a messy reaction.
The possibility of a reaction by other weak bases such as
NaHCO3, Na2CO3 and K2CO3 was also explored, but after
48 h the reaction had not been completed and most of the
starting material was recovered. It is noteworthy that using
chloroacetic acid instead of bromoacetic acid in this two-
step reaction gave lower overall yield.
We also attempted to use benzaldehyde deriva-
tives instead of 2-formylindole in the Ugi coupling.
For instance, the reactions of 4-chloro-, methoxy-, and
1 3

J IRAN CHEM SOC
Table 1 Cyclization of
Ugi-adduct in the presence of
Cs2CO3
Run
1
Ugi-adducta
Pyrazinoindoleb
Isolated
yield
(%)
Piperazin-2-one
Isolated
yield
(%)
(Isolated yield %)
82
17
O
O
O
N
NH
NH
N
H
N
N
H
N
N
N
O
O
O
Br
2.2a
2.2b
1.2
(88)
2
55
trace
O
O
O
NH
N
NH
N
H
N
N
N
N
N
O
H
O
O
Br
2.3ad
1.3c
2.3b
(81)
3
59
10
O
O
O
N
NH
NH
N
N
N
N
OMe
N
N
OMe
H
H
O
O
O
Br
MeO
2.4a
2.4b
1.4
(78)
a
Ugi-adducts were
4
62
trace
synthesized from the reaction
of 2-formylindole (1 equiv.),
amine (1 equiv.), bromoacetic
acid (1 equiv.) and isocyanide
(1 equiv.) in MeOH at room
temperature after 24 h
O
O
O
N
N
NH
NH
N
N
N
N
N
H
H
O
O
O
Br
2.5a
2.5b
b
1.5
Ugi-adduct (0.5 mmol),
Cs2CO3 (0.5 mmol) and 10 ml
DMF at room temperature
(68)
5
50
14
c
Compound 1.3 is obtained
O
O
O
NH
NH
N
as a 50:50 mixture of
diastereomers (detected by
NMR)
N
N
N
N
N
H
N
H
O
Ph
Ph
O
O
Ph
d
Br
Compound 2.3a is obtained
2.6a
2.6b
1.6
as a 83:17 mixture of
diastereomers (detected by
NMR)
(91)
methyl-benzaldehyde, as aldehyde sources, aniline, o-
and p-toluidine, p-anisidine and p-bromoaniline as amine
sources, and bromoacetic acid and cyclohexyl isocyanide
gave the wide range of corresponding Ugi compounds 3a–
3k. Unexpectedly, these compounds remained unchanged
in the presence of Cs2CO3 in DMF at room temperature,
even after 24 h (Scheme 2). Raising the temperature of the
reaction gave a mixture of unidentified compounds. It is
worth mentioning that the similar Ugi-adducts (Cl instead
of Br) in ethanolic potassium hydroxide solution under
ultrasonic conditions properly underwent cyclization to
form 2,5-diketopiperazines [31].
The structures of all new compounds were character-
1
ized by FT-IR, H NMR, 13C NMR and CHN analysis.
1
For example the H NMR spectra clearly demonstrated
the removing of N–H in indole for 2.1a and N–H in amide
for 2.1b. Diastereotopic protons in CH2 at α-position of
carbonyl for both 2.1a and 2.1b are split as quartet and
appeared in 4.93 ppm (J = 16.77, 12.06 Hz) and 3.93 ppm
(J = 16.90, 24.44 Hz), respectively. Proton of CO–NH-
appears as doublet in 5.58 ppm (J = 7.40 Hz) for 2.1a
and the N–H of indole appears as singlet at 8.61 ppm for
2.1b. The two related carbonyl groups in both 2.1a and
2.1b show two carbon peaks at 167.1 and 166.2 ppm in
1 3

J IRAN CHEM SOC
O
O
O
O
NH
NH
NH
NH
Cl
Cl
Cl
Cl
N
N
Br
N
N
O
O
O
O
Br
Br
Br
Br
3a
3b
3c
3d
O
O
O
O
NH
NH
NH
NH
MeO
MeO
MeO
N
N
Br
N
N
O
O
O
O
Br
Br
Br
Br
3e
3f
3g
3h
O
O
O
NH
NH
NH
MeO
N
N
OMe
N
Br
O
O
O
Br
Br
Br
3i
3j
3k
Scheme 2 Benzaldehyde derivatives of Ugi-adducts which were unreactive at room temperature in the presence of Cs2CO3
the 13C NMR spectra for 2.1a and two peaks at 165.2 and
164.5 ppm for 2.1b. Three sp3 carbon atoms which are
adjacent to nitrogen appear in 63.6, 49.2 and 47.1 ppm for
2.1a and 63.6, 49.2 and 47.1 ppm for 2.1b. The indole N–H
in 2.1a and the amide N–H in 2.1b show FT-IR peaks at
3,313 and 3,315 cm−1, respectively. The infrared spectra
also confirmed the existence of C=O in both 2.1a and 2.1b
with absorptions at 1,655 and 1,669 cm−1, respectively.
Acknowledgments We thank Alzahra University and Iran National
Science Foundation (INSF) for financial support to our research
group. We thank the Catalysis and Peptide Research Unit (http://cpr
u.ukzn.ac.za/Homepage.aspx) at UKZN for assistance with the NMR
analysis of these compounds.
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In conclusion, we observed that 2-formylindole, bro-
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1 3