A three-component, intramolecular Ugi reaction toward unique indoloketopiperazines

Article abstract of DOI:10.1016/j.tetlet.2012.04.090

2-(3-Chloro-2-formyl-1H-indol-1-yl) acetic acid, as a bifunctional formyl-acid, is prepared in three steps. This compound undergoes a one-pot, four-center, three-component Ugi reaction with primary amines and alkyl isocyanides. A series of novel substituted indoloketopiperazine derivatives are obtained in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2012.04.090

Tetrahedron Letters 53 (2012) 3353–3356
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A three-component, intramolecular Ugi reaction toward unique
indoloketopiperazines
⇑
Mehdi Ghandi , Nahid Zarezadeh, Abuzar Taheri
School of Chemistry, College of Science, University of Tehran, Tehran, PO Box 14155 6455, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(3-Chloro-2-formyl-1H-indol-1-yl) acetic acid, as a bifunctional formyl-acid, is prepared in three steps.
This compound undergoes a one-pot, four-center, three-component Ugi reaction with primary amines
and alkyl isocyanides. A series of novel substituted indoloketopiperazine derivatives are obtained in mod-
erate to high yields.
Received 15 February 2012
Revised 14 March 2012
Accepted 19 April 2012
Available online 25 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ugi reactions
Indoloketopiperazines
Isocyanides
Multicomponent reactions (MCRs)1 and isocyanide-based mul-
ticomponent reactions (IMCRs)2 have emerged as efficient and
powerful tools for the synthesis of highly complex natural and
diverse drug-like compounds. The most popular IMCR is probably
the Ugi reaction, in which a carboxylic acid, a primary amine, an
aldehyde, and an isocyanide react in a one-pot manner to afford
an N-substituted acyl aminoamide containing four independently
varying groups in one reaction.3 Utilization of bifunctional
reagents, in which the participating functional groups of two
components of the U-4CR are present in one structure, is another
strategy to increase scaffold diversity.4
The indole nucleus is an important subunit present in many bio-
logically active natural products.5 Compounds possessing an indole
moiety show antitumor activity,6 and vesication to human skin.7
Due to their binding with high affinity to many receptors, substi-
tuted indoles have been referred to as privileged structures.8 On
the other hand, piperazines, and their keto analogues are among
the most important backbones in drug discovery.9 Piperazines
are a class of compounds which are present in molecules involved
in the regulation of a wide variety of biological processes.10
The known antidepressant,11 anti-inflammatory12 and anti-
obesity13 properties of pyrazino-indoles along with the docu-
mented antitumor activity of compound 1, especially against colon
and lung tumors (Fig. 1),14 prompted us to undertake a study on
the synthesis of fused tricyclic scaffolds 2a–k as the respective
analogues of 1, in which the bioactive ketopiperazine motif is fused
with an indole moiety. As part of our interest in Ugi reactions,15
herein, we describe the synthesis of a new series of fused indolo-
ketopiperazines via the four-center, three-component Ugi reaction
of 2-(3-chloro-2-formyl-1H-indol-1-yl)acetic acid (3) with various
amines and isocyanides.
The aldehyde-acid 3 chosen for this study was synthesized
according to the procedure presented in Scheme 1. Initially, 3-
chloro-1H-indole-2-carbaldehyde (4) was synthesized using a pre-
viously reported procedure.16 Subsequent treatment of 4 with
methyl chloroacetate in the presence of K2CO3 in refluxing MeCN
for 6 h afforded methyl 2-(3-chloro-2-formyl-1H-indol-1-yl)ace-
tate (5) in 90% yield.17 Transformation of 2 into acid 3 was then
carried out in methanolic NaOH at room temperature in 85% yield
over 4 h.18
In a model experiment, formyl-acid 3 was treated with p-tolui-
dine and tert-butyl isocyanide. The reaction proceeded smoothly
and was complete within 4 h at 40 °C, affording 2a in 90% yield
(Scheme 2).19
R1
R1
R3
Cl
HN
O
N
O
R2
R2
N
N
O
N
R4
1
2a-k
⇑
Corresponding author. Tel.: +98 21 61112250; fax: +98 21 66495291.
E-mail address: ghandi@khayam.ut.ac.ir (M. Ghandi).
Figure 1. The known anti-colon and lung tumors pyrazinoindoles (1) and the
unique indoloketopiperazines 2a–k as the respective analogues.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.090

3354
M. Ghandi et al. / Tetrahedron Letters 53 (2012) 3353–3356
Cl
O
Cl
Cl
O
H
O
H
MeOCOCH2Cl
N
N
H
N
NaOH, MeOH
K2CO3, MeCN
H
O
rt, 4 h
O
reflux, 6 h
85%
90%
OMe
OH
4
5
3
Scheme 1. Synthesis of formyl acid 3.
Me
Cl
Me
O
Subsequent reaction of various amines and commercially avail-
able 1,1,3,3-tetramethylbutyl, tert-butyl, or cyclohexyl isocyanides
under the described conditions afforded the indoloketopiperazines
2a–k in moderate to high yields (Table 1).20
As has been rationalized in Scheme 3, it is conceivable that the
initial event is the formation of iminium ion 6 from the amine, and
formyl-acid 3 followed by activation of the imine by the carboxylic
acid. Subsequent addition of the nucleophilic isocyanide to the
activated iminium species followed by trapping of the nitrilium
intermediate by the carboxylate affords the iminolactone 7. The
irreversible acyl transfer step (Mumm rearrangement) associated
with the Ugi reaction finally gives the desired indoloketopipera-
zines 2a–k.
In conclusion, using a bifunctional starting material containing
an aldehyde and carboxylic acid functional group in Ugi 3CC reac-
tions leads to a variety of novel heteroaryl-fused substituted indo-
loketopiperazine derivatives 2a–k. The method offers several
advantages including moderate to high yields of products and an
easy experimental work-up procedure. These new structures
broaden the scaffolds accessible through Ugi reactions, and many
of them may represent interesting pharmacophores.
Me
O
H
NH2
Me
Cl
Me
Me
NH
MeOH
N
Me
NC
+
+
N
N
O
40 °C, 4 h
90%
O
Me
OH
3
2a
Scheme 2. Synthesis of indoloketopiperazine 4a.
The structure of 2a was confirmed on the basis of analytical
data.19 For example, the mass spectrum of 2a displayed the molec-
ular ion peak at 409. The IR spectrum displayed characteristic
absorption bands at 3310 and 1684 cmÀ1 due to N–H and C@O
stretching vibrations, respectively. The 1H NMR spectrum of 2a dis-
played singlets at d 1.33 (9H, s, CMe3) and d 2.42 (3H, s, Me) along
with a singlet at d 5.32 (1H, s, NCOCHN) and an AB quartet at d 5.05
(2H, J = 16.5 Hz, NCH2CO), representing the ketopiperazine ring
protons. This reaction demonstrated that substituted indoloketo-
piperazine derivatives could be prepared through a four center,
three-component condensation (3CC) Ugi reaction.
Table 1
Structures and yields of compounds 2a–k obtained from 3CC Ugi reactions
Entry
R1NH2
R2NC
Product
Time (h)
Yield (%)
NH2
Me
Me
Me
Me
Me
Cl
O
N
O
2a
Me
NC
NC
NH
N
1
4
90
Me
Me
NH2
Cl
Cl
O
NH
N
2
4
83
Me
N
Me
O
2b
NH2
Me
Me
Me
Me Me
Me
Me
Me
Me
Me
Me
NC
O
NH
3
4
89
N
N
O
Me
2c
NH2
Me
NC
Cl
O
NH
Me
N
N
4
4
85
Me
O
Me
2d

M. Ghandi et al. / Tetrahedron Letters 53 (2012) 3353–3356
3355
Table 1 (continued)
Entry
R1NH2
R2NC
Product
Time (h)
Yield (%)
NH2
Me
Me
Me
Me
Me
Me
Me
Me Me
Me
NC
Cl
O
N
NH
M
e
Me
N
5
4
87
Me
O
Me
2e
NH2
NC
Cl
O
NH
6
8
73
N
N
O
2f
NH
NH
2
NC
Cl
Cl
Cl
O
NH
7
10
60
N
N
O
2g
Cl
Me
Me
Me
Me
Me
Me
Me
2
Me
Cl
NC
O
N
NH
Me Me
8
9
N
10
65
90
O
2h
Cl
NH
2
Me
Me
Me
Cl
Me
NC
NC
O
Me
NH
Me
Me
N
6
N
Me
O
2i
NH
2
Cl
O
NH
Me
10
11
6
6
88
92
N
N
O
2j
Me
Me
Me
NH
Me
Me
Me Me
Me
Me
Me
2
Me
Cl
NC
O
N
NH
N
Me
O
Me
2k
H
N
Cl
R2
NH
Cl
Cl
R1
Cl
R2
N
O
H
O
HN
O
N
N
H
N
R1
N
R1-NH2
R1
Mumm
N
R2-NC
O
O
O
OH
O
O
3
6
7
2a-k
Scheme 3. Proposed mechanism for the formation of 2a–k.

3356
M. Ghandi et al. / Tetrahedron Letters 53 (2012) 3353–3356
Tseng, Y.-C.; Wang, J.; Wasti, R.; Werneburg, B.; Wua, J. P.; Xiong, Z. Bioorg. Med.
Acknowledgment
Chem. Lett. 2008, 18, 938–941.
13. Röver, S.; Adams, D. R.; Bénardeau, A.; Bentley, J. M.; Bickerdike, M. J.; Bourson,
A.; Cliffe, I. A.; Coassolo, P.; Davidson, J. E. P.; Dourish, C. T.; Hebeisen, P.;
Kennett, G. A.; Knight, A. R.; Malcolm, C. S.; Mattei, P.; Misra, A.; Mizrahi, J.;
Muller, M.; Porter, R. H. P.; Richter, H.; Taylor, S.; Vickers, S. P. Bioorg. Med.
Chem. Lett. 2005, 15, 3604–3608.
The authors acknowledge the University of Tehran for financial
support of this research.
14. Menta, E.; Nicotra, F.; Pescalli, N.; Spinelli, S. WO 01/09136 A1, 2001; Chem.
Abstr., 2001, 134, 63063x.
Supplementary data
15. (a) Ghandi, M.; Zarezadeh, N.; Taheri, A. Tetrahedron Lett. 2011, 52, 1228–1232;
(b) Ghandi, M.; Zarezadeh, N.; Taheri, A. Tetrahedron 2010, 66, 8231–8237; (c)
Ghandi, M.; Asgari, P.; Taheri, A.; Abbasi, A. Cent. Eur. J. Chem. 2010, 8, 899–905.
16. Majoand, V. J.; Perumal, P. T. J. Org. Chem. 1996, 61, 6523–6525.
17. Preparation of methyl 2-(3-chloro-2-formyl-1H-indol-1-yl)acetate (5). To a
Supplementary data associated with this article can be found, in
the onlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.04.090.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
solution of
4 (2.68 g, 15 mmol) in MeCN (30 mL) were added methyl
chloroacetate (1.65 g, 15.2 mmol) and K2CO3 (2.10 g, 15 mmol) and the
mixture was heated at reflux for 6 h. The resulting solid was filtered, and the
filtrate concentrated under reduced pressure to afford 3.39 g (90%) of 5. Brown
oil. 1H NMR (500 MHz, CDCl3) d 3.80 (3H, s, OMe), 5.35 (2H, s, CH2CO2), 7.24–
7.35 (2H, m, Ar), 7.53 (1H, t, J = 7.2 Hz, Ar), 7.82 (1H, d, J = 7.7 Hz, Ar), 10.19 (1H,
s, COH); 13C NMR (125 MHz, CDCl3) d 45.9 (CH2CO2), 5.26 (OMe), 109.9, 120.8,
122.0, 124.4, 124.6, 128.7, 129.2, 138.4 (C-Ar), 168.7 (C@O), 181.2 (C@O); IR
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(24), 222 (28), 216 (6), 204 (12), 192 (59), 177 (14), 164 (15), 123 (20%). Anal.
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(7 mL) was added dropwise. The mixture was stirred for 4 h at rt (TLC
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(500 MHz, CDCl3) d 5.16 (2H, s, CH2CO2H), 7.15 (1H, t, J = 7.5 Hz, Ar), 7.23 (1H,
d, J = 8.2 Hz, Ar), 7.36 (1H, t, J = 7.5 Hz, Ar), 7.64 (1H, d, J = 8.2 Hz, Ar), 10.03 (1H,
s, COH); 13C NMR (125 MHz, CDCl3) d 46.3 (CH2CO2H), 110.6, 120.9, 122.2,
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124.4, 124.7, 128.9, 129.2, 138.8 (C-Ar), 170.5 (C@O), 181.3 (C@O); IR (KBr)
t:
2482–2955, 1754 cmÀ1; MS (EI) m/z: 239 (M+ 37Cl], 17), 237 (M+ 35Cl], 55),
[
[
192 (100), 164 (41), 128 (35), 123 (90%). Anal. Calcd for C11H8ClNO3: C, 55.60;
H, 3.39; N, 5.89. Found: C, 55.49; H, 3.41; N, 6.14.
19. Representative procedure for the preparation of compound 2a: A solution of
formyl-acid
3 (0.24 g, 1.0 mmol), toluidine (1.0 mmol) and tert-butyl
isocyanide (1.0 mmol) in MeOH (3 mL) was stirred at 40 °C for 4–10 h. After
completion of the reaction as indicated by TLC, the precipitate was filtered and
recrystallized from EtOH to give N-tert-butyl-10-chloro-3-oxo-2-p-tolyl-1,2,3,4-
tetrahydropyrazino[1,2-a]indole-1-carboxamide (2a) as a white solid (0.37 g,
90%); mp 251–253 °C; 1H NMR (500 MHz, CDCl3) d 1.33 (9H, s, CMe3), 2.42 (3H,
s, Me), 5.05 (2H, AB-q, J = 16.5 Hz, NCH2CO), 5.32 (1H, s, NCOCHN), 5.82 (1H, br
s, NH), 7.26 (2H, d, J = 8.3 Hz, Ar), 7.30 (2H, d, J = 8.3 Hz, Ar), 7.38–7.44 (3H, m,
Ar), 7.38 (1H, d, J = 7.9 Hz, Ar); 13C NMR (125 MHz, CDCl3) d 21.2 (Me), 28.5
(CMe3), 46.9 (NCH2CO), 52.5 (CMe3), 62.0 (NCOCHN), 99.9, 109.4, 118.4, 121.2,
123.4, 124.9, 125.4, 126.9, 130.3, 134.0, 138.1, 138.4 (C-Ar), 165.8 (C@O), 165.9
(C@O); IR (KBr)
[
t [
: 3310, 1684 cmÀ1; MS (EI) m/z: 411 (M+ 37Cl], 2), 409 (M+
35Cl], 6), 374 (9), 309 (100), 281 (38), 167 (29), 149 (90), 57 (26%). Anal. Calcd
for C23H24ClN3O2: C, 67.39; H, 5.90; N, 10.25. Found: C, 67.77; H, 5.90; N, 10.30.
20. 10-Chloro-N-cyclohexyl-2-(3,4-dimethylphenyl)-3-oxo-1,2,3,4-
tetrahydropyrazino[1,2-a]indole-1-carboxamide (2d): White solid (0.38 g, 85%);
mp 254–256 °C; 1H NMR (500 MHz, CDCl3) d 1.07–1.92 (10H, m, 5CH2 of
cyclohexyl), 2.27 (6H, s, 2Me), 3.66–3.72 (1H, m, CHNH of cyclohexyl), 5.02 (2H,
AB-q, J = 16.5 Hz, NCH2CO), 5.39 (1H, s, NCOCHN), 6.29 (1H, d, J = 8.1 Hz, NH),
7.06 (1H, d, J = 8.0 Hz, Ar), 7.11 (1H, s, Ar), 7.20 (1H, d, J = 8.0 Hz, Ar), 7.23–7.32
(3H, m, Ar), 7.62 (1H, d, J = 7.9 Hz, Ar); 13C NMR (125 MHz, CDCl3) d 19.5 (Me),
19.9 (Me), 24.5 (2CH2), 25.3 (CH2), 32.5 (CH2), 32.9 (CH2), 47.0 (NCH2CO), 49.3
(CHNH of cyclohexyl), 61.5 (NCOCHN), 100.0, 109.4, 118.4, 121.2, 123.5, 124.2,
124.8, 125.3, 128.0, 130.8, 134.0, 137.1, 138.2, 138.4 (C-Ar), 165.8 (C@O), 166.1
(C@O); IR (KBr)
[
t
: 3307, 1683 cmÀ1; MS (EI) m/z: 451 (M+
[
37Cl], 2), 449 (M+
35Cl], 6), 414 (8), 323 (100), 295 (29), 144 (11), 55 (14%). Anal. Calcd for
C
26H28ClN3O2: C, 69.40; H, 6.27; N, 9.34. Found: C, 69.43; H, 6.20; N, 9.39. 10-
Chloro-2-(4-methylbenzyl)-3-oxo-N-(2,4,4-trimethylpentan-2-yl)-1,2,3,4-
tetrahydropyrazino[1,2-a]indole-1-carboxamide (2k). Cream solid (0.44 g, 92%);
mp 196–198 °C; 1H NMR (500 MHz, CDCl3) d 0.92 (9H, s, CMe3), 1.33 and 1.34
(6H, 2s, CMe2), 1.69 (2H, AB-q, J = 15.0 Hz, CCH2C), 2.38 (3H, s, Me), 4.16 (1H, d,
J = 15.1 Hz, CHHPh), 4.94 (2H, AB-q, J = 16.6 Hz, NCH2CO), 5.00 (1H, s,
NCOCHN), 5.34 (1H, d, J = 15.1 Hz, CHHPh), 5.72 (1H, br s, NH), 7.20 (4H, s,
Ar), 7.25–7.35 (3H, m, Ar), 7.62 (1H, d, J = 7.9 Hz, Ar); 13C NMR (125 MHz,
CDCl3) d 21.1 (Me), 28.6 (CMe2), 29.4 (CMe2), 31.2 (CMe3), 31.5 (CCH2C), 46.5
(NCH2CO), 49.0 (CH2Ph), 51.7 (CMe3), 56.4 (CMe2), 56.9 (NCOCHN), 100.0,
109.3, 118.3, 121.1, 123.4, 124.7, 125.3, 128.4, 129.6, 132.0, 133.9, 137.8 (C-Ar),
11. Bös, M.; Jenck, F.; Moreau, J. L.; Mutel, V.; Sleight, A. J.; Widmer, U. Eur. Med.
Chem. 1997, 32, 253–261.
12. Goldberg, D. R.; Choi, Y.; Cogan, D.; Corson, M.; DeLeon, R.; Gao, A.;
Gruenbaum, L.; Hao, M. H.; Joseph, D.; Kashem, M. A.; Miller, C.; Moss, N.;
Netherton, M. R.; Pargellis, C. P.; Pelletier, J.; Sellati, R.; Skow, D.; Torcellini, C.;
165.0 (C@O), 165.9 (C@O); IR (KBr) t
: 3356, 1691 cmÀ1; MS (EI) m/z: 480 (M+,
4), 444 (9), 323 (80), 105 (100), 57 (49%). Anal. Calcd for C28H34ClN3O2: C,
70.06; H, 7.14; N, 8.75. Found: C, 70.04; H, 6.86; N, 8.90.