A novel intramolecular Ugi 3CC for the synthesis of N-alkyl-3-oxo-2-aryl-1, 2,3,4-tetrahydropyrazino[1,2-a]indole-1-carboxamides

Article abstract of DOI:10.1016/j.tetlet.2012.05.036

An intramolecular Ugi reaction of 2-(2-formyl-1H-indol-1-yl)acetic acid with aryl amines and isocyanides has been developed to produce a novel class of N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-1-carboxamides in good yields. This is the

Full text of DOI:10.1016/j.tetlet.2012.05.036

Tetrahedron Letters 53 (2012) 3676–3679
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A novel intramolecular Ugi 3CC for the synthesis of N-alkyl-3-oxo-2-aryl-1,2,3,
4-tetrahydropyrazino[1,2-a]indole-1-carboxamides
B.V. Subba Reddy a, , Sujit Kumar Dey a, J.S. Yadav a, B. Sridhar b
⇑
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An intramolecular Ugi reaction of 2-(2-formyl-1H-indol-1-yl)acetic acid with aryl amines and isocyanides
Received 1 March 2012
Revised 2 May 2012
Accepted 5 May 2012
Available online 12 May 2012
has been developed to produce
a novel class of N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazino
[1,2-a]indole-1-carboxamides in good yields. This is the first report on intramolecular Ugi three compo-
nent reaction of 2-(2-formyl-1H-indol-1-yl)acetic acid, aryl amine, and isonitrile.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ugi 3CC reaction
2-(2-Formyl-1H-indol-1-yl)acetic acid
Aryl amine
Isonitrile
Tetrahydropyrazino[1,2-a]indole-1-
carboxamide
O
Multi-component reactions (MCRs) are extremely important
owing to their wide range of applications in medicinal chemistry
for the production of diversified structural scaffolds and combina-
torial synthesis.1 The advantages of MCRs are the formation of sev-
eral bonds with a high degree of selectivity and atom efficiency by
a single-step process.2 Among MCRs, the Ugi3 and the Passerini
reactions,4 have been among the most extensively employed in
an industrial context.5,6 A new version of isocyanide-based MCRs
with keto acids has been developed as bifunctional reagents.7,8 In
OH
NH2
Ph
O
N
N
O
MeOH
+
NC
H
N
Reflux, 3h
NH
O
4e
3
1
2
Scheme 2. Preparation of 4e via Ugi 3CC reaction.
(a) LAH, THF, 0 °C-rt, 3h
CO2Et
CHO
N
H
(b) IBX/DMSO, rt, 30 min
90% over two steps
N
H
(a) NaH/DMF
(b) BrCH2CO2Et
0°C-r.t, 1.5h
85%
LiOH
CHO
CO2H
CHO
N
N
THF:H2O (8:2)
95%
rt, 1h,
CO2Et
1
( )
Scheme 1. Preparation of starting aldehydo acid (1).
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
Figure 1. X-ray crystal structure of 4g.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.036

B. V. Subba Reddy et al. / Tetrahedron Letters 53 (2012) 3676–3679
3677
Table 1
scaffolds with various biological activities such as antidepressants,
anxiolytics, anticonvulsants, and protein kinase C inhibitors.9
Therefore, the development of novel MCRs provides a new avenue
to generate new chemical entities for medicinal chemists.10–12
Following our interest on multi-component reactions,13 we
herein describe a novel three-component reaction for the synthesis
of N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-
1-carboxamide derivatives via the Ugi 3CC reaction.
Optimization of the solvent and temperature
O
O
Ph N
N
NH2
HO
O
+
N
O
Solvent, T °C
NC
NH
H
The desired starting material, 2-(2-formyl-1H-indol-1-yl)acetic
acid (1) for this study was synthesized according to the procedure
presented in Scheme 1.
Accordingly, treatment of 2-(2-formyl-1H-indol-1-yl)acetic acid
(1), t-butyl isocyanide (2), and aniline (3) in methanol at reflux
temperature gave the corresponding product 4e in 82% yield
(Scheme 2).
The structure of 4e was characterized and confirmed by spectral
data. The structure of the product 4g was further confirmed by the
X-ray crystallography (Fig. 1).14
Entry
Solvent
T (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
Toluene
THF
Toluene
Benzene
DCM
CH3CN
EtOAc
DMF
MeOH
MeOH
40
40
110
80
24
24
10
10
8
5
9
12
8
3
20
<20
35
30
50
70
20
42
60
72b
40
82
77
60
40
70
10
Next, we studied the effect of solvent and temperature in the
coupling of 2-(2-formyl-1H-indol-1-yl)acetic acid (1), t-butyl iso-
cyanide (2), and aniline (3) (Table 1). As shown in Table 1, metha-
nol gave the best result at 70 °C in a short reaction time.
Encouraged by the above result, we extended this process for dif-
ferent substrates. Interestingly, various aromatic amines such as
a
Isolated yield after column chromatography.
Though reaction proceeds smoothly at 40 °C, the best yield was obtained at 70 °C.
b
particular, indole based bifunctional reagents are very useful as
they provide pyrazino-indole derivatives which are important
Table 2
Ugi reaction for N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-1-carboxamide
Entry
Aryl amine (3)
NH2
Isonitrile (2)
Producta (4)
Time (h)
2.5
Yieldb (%)
NC
O
N
NH
Me
a
82
N
Me
OMe
Cl
O
NH2
NC
NC
O
NH
MeO
b
c
5.0
4.0
3.0
72
75
N
N
N
O
NH2
O
NH
Cl
N
O
NC
NH2
O
NH
Ph
d
85
72
N
N
N
N
O
NH2
O
NC
NC
NH
Ph
e
3.0
4.0
N
O
O
Cl
NH2
NH
f
65
N
O
Cl
(continued on next page)

3678
B. V. Subba Reddy et al. / Tetrahedron Letters 53 (2012) 3676–3679
Table 2 (continued)
Entry
Aryl amine (3)
NH2
Isonitrile (2)
Producta (4)
Time (h)
3.5
Yieldb (%)
O
NC
NH
Ph
g
h
i
87
N
N
O
NH2
O
NC
NH
Ph
4.0
3.5
70
80
N
N
O
NH2
NH2
O
NC
NH
Me
Me
N
N
N
Me
Me
O
O
O
S
NC
N
H
Ts
O
N
j
7.0
70
O
Me
a
All products were characterized by NMR, IR, and mass spectroscopy.
Isolated yields after chromatography.
b
The scope and generality of this process are illustrated with re-
spect to various aldehydes and isonitriles and the results are pre-
sented in Table 2.15
In summary, we have developed a simple and efficient strategy
for the synthesis of N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazi-
no[1,2-a]indole-1-carboxamide derivatives in good yields from
readily available precursors under neutral conditions. It is a very
useful strategy to produce tetrahydropyrazino-indole derivatives
in a single-step process.
N
R
H
R-NH2
R'-NC
N
N
N
O
CO2H
I
( )
CO2H
:
NHR
HN
O
R
N
N
R'
III
(
)
O
II
( )
N
R'
O
O
Acknowledgements
O
NHR'
S.D. thanks CSIR, New Delhi for the award of a fellowship. The
author acknowledges the partial support by King Saud University
for Global Research Network for Organic Synthesis (GRNOS).
N
N
R
O
References and notes
Scheme 3. A plausible reaction pathway.
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V. G.; Reznichenko, A. L.; Balenkova, E. S. Tetrahedron 2007, 63, 3031; (e) Ilyn, A.
4-methyl-, 4-methoxy-, 4-chloro-, and 2-chloroaryl amines under-
went smooth coupling with an aldehydo acid (1) and isonitriles to
furnish a variety of aryl substituted pyrazino-indole derivatives
(Table 2, entries a–c, f, i, and j). The reaction was quite successful
with different isonitriles such as cyclohexyl isocyanide, t-butyl iso-
cyanide, 1,1,3,3-tetramethylbutyl isocyanide, and tosylmethyl iso-
cyanide (Table 2, entries a–j). The reaction also proceeded
smoothly with benzyl amine (Table 2, entries d and g). All the
products were characterized and confirmed by NMR, IR, and mass
spectrometry.
Mechanistically, we assume that the reaction proceeds via the
formation of imine (I) in situ from indole aldehydo acid and aryl
amine. Subsequent attack of isocyanide on imine would give the
intermediate (II) which subsequently forms iminolactone (III) that
undergoes an intramolecular cyclization with a secondary amine to
afford the six-membered lactam as depicted in Scheme 3.

B. V. Subba Reddy et al. / Tetrahedron Letters 53 (2012) 3676–3679
3679
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U.S. Pat. 022778, 1977; Chem. Abstr. 1977, 87, 68421q.; (g) Commons, T. J.;
Laclair, C. M.; Christman S. PCT Int. Appl. WO 9612721, 1996; Chem. Abstr.
1996, 125, 114494u.
temperature and the crude product was purified by column chromatography
using ethyl acetate/n-hexane. Spectral data for selected compounds: 4b: White
solid, mp 238–241 °C. IR (KBr):
tmax 3450, 2926, 2855, 1743, 1663, 1057, 1460,
1245, 760 cmÀ1 1H NMR (300 MHz, CDCl3 + DMSO-d6): d 8.04 (d, J = 7.7 Hz,
;
1H), 7.78 (s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.32 (m, 1H), 7.17 (d, J = 8.6 Hz, 2H),
7.09–7.01 (m, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.47 (s, 1H), 5.53 (s, 1H), 4.98 (d,
J = 16.6 Hz, 1H), 4.89 (d, J = 16.6 Hz, 1H), 3.82 (m, 3H), 3.52 (m, 1H), 2.36–1.38
(m, 10H). 13C NMR (75 MHz, CDCl3 + DMSO-d6): d 167.1, 166.3, 159.0, 135.1,
133.5, 129.1, 128.2, 124.9, 122.3, 120.8, 120.6, 114.7, 109.0, 97.4, 63.7, 55.4,
49.2, 47.0, 32.4, 29.6, 27.1, 26.3, 25.2. LC–MS: m/z: 440 (M+Na). HRMS Calcd for
C
25H27N3O3Na: 440.1950. Found: 440.1971. Compound 4g: White solid, mp
190–193 °C; IR (KBr): tmax 3441, 3277, 2925, 1692, 1643, 1555, 1220,
734 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.51 (d, J = 8.3 Hz, 1H), 7.35–7.22 (m,
;
7H), 7.19 (d, J = 8.3 Hz, 1H), 7.14–7.06 (m, 1H), 6.28 (s, 1H), 5.45 (m, 2H), 4.92
(d, J = 16.6 Hz, 1H), 4.83 (d, J = 16.6 Hz, 1H), 4.12 (m, 1H), 1.24 (s, 9H). 13C NMR
(75 MHz, CDCl3): d 166.9, 165.6, 135.8, 134.8, 129.4, 128.0, 127.7, 127.0, 121.1,
120.0, 119.6, 108.4, 96.7, 58.1, 50.0, 48.1, 45.8, 28.0. LC–MS: m/z: 398 (M+Na).
HRMS Calcd for C23H25N302Na: 398.1844. Found: 398.1840. Compound 4h:
10. Ilyin, A. P.; Parchinski, V. Z.; Peregudova, J. N.; Trifilenkov, A. S.; Poutsykina, E.
B.; Tkachenko, S. E.; Kravchenkoa, D. V.; Ivachtchenko, A. V. Tetrahedron Lett.
2006, 47, 2649.
11. (a) Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R. Org.
Lett. 2008, 10, 2581; (b) Reddy, B. V. S.; Majumdar, N.; Gopal, A. V. H.;
Chatterjee, D.; Kunwar, A. C. Tetrahedron Lett. 2010, 51, 6835.
12. (a) Tsaloev, A.; Ilyin, A.; Tkachenko, S.; Ivachtchenko, A.; Kravchenko, D.;
Krasavin, M. Tetrahedron Lett. 2011, 52, 1800; (b) Ghandi, M.; Zarezadeh, N.;
Taheri, A. Tetrahedron Lett. 2011, 52, 1228.
White solid, mp 200–202 °C. IR (KBr):
tmax 3328, 2948, 1686, 1644, 1541, 1423,
1223, 738 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.56 (d, J = 7.5 Hz, 1H), 7.44–7.09
.
(m, 9H), 6.36 (s, 1H), 5.45 (s, 1H), 5.00 (d, J = 16.6 Hz, 1H), 4.94 (d, J = 16.6 Hz,
1H), 1.68 (d, J = 15.1 Hz, 1H), 1.56 (d, J = 15.1 Hz, 1H), 1.30 (s, 6H), 0.81 (s, 9H).
13C NMR (75 MHz, CDCl3): d 166.4, 166.1, 140.9, 129.4, 128.9, 128.0, 127.0,
122.2, 120.8, 120.5, 108.9, 97.5, 64.0, 56.2, 51.7, 47.0, 31.3, 31.1, 28.7, 28.5. LC–
13. (a) Yadav, J. S.; Reddy, B. V. S.; Reddy, Y. J.; Reddy, N. S. Tetrahedron Lett. 2009,
50, 2877; (b) Yadav, J. S.; Reddy, B. V. S.; Biswas, S. K.; Sengupta, S. Tetrahedron
Lett. 2009, 50, 5798; (c) Yadav, J. S.; Reddy, B. V. S.; Reddy, G. M.; Anjum, S. R.
Tetrahedron Lett. 2009, 50, 6029; (d) Reddy, B. V. S.; Majumdar, N.; Rao, T. P.;
Sridhar, B. Tetrahedron Lett. 2012, 53, 2273.
MS: m/z: 440 (M+Na). HRMS Calcd for
440.2251. Compound 4j: White solid, mp 245–247 °C. IR (KBr): tmax 3387,
3218, 2924, 1694, 1654, 1316, 1140, 1023, 751 cmÀ1 1H NMR (500 MHz,
C26H31N3O2Na: 440.2246. Found:
.
CDCl3 + DMSO-d6): d 7.60 (d, J = 8.0 Hz, 1H), 7.52–7.43 (m, 1H), 7.23–7.19 (m,
2H), 7.16 (d, J = 8.0 Hz, 2H), 7.13–7.09 (m, 1H), 7.07 (d, 2H), 6.93 (d, J = 8.0 Hz,
2H), 6.61 (s, 1H), 6.41 (d, J = 8.0 Hz, 2H), 5.50 (s, 1H), 4.82 (m, 1H), 4.70 (d,
J = 16.0 Hz, 1H), 4.29 (d, J = 16.0 Hz, 1H), 4.18–4.05 (m, 1H), 2.25 (s, 3H), 2.08 (s,
3H); 13C NMR (75 MHz, CDCl3): d 167.2, 164.9, 143.1, 136.1, 134.2, 132.4,
128.6, 127.7, 127.0, 124.9, 119.8, 119.3, 120.9, 107.7, 97.3, 60.2, 59.0, 45.5, 28.2.
LC–MS: m/z: 510 (M+Na). HRMS Calcd for C27H25N304SNa: 510.1463. Found:
510.1456.
14. CCDC868310 contains supplementary crystallographic data for the structure 4g.
15. Typical procedure:
A solution of 2-(2-formyl-1H-indole-1-yl) acetic acid
(203 mg, 1 mmol), p-methoxy aniline (123 mg, 1.0 mmol), and cyclohexyl
isocyanide (109 mg, 1.0 mmol) in methanol (4 mL) were heated under reflux
for the appropriate time (see Table). The progress of the reaction was
monitored by TLC. Upon completion, the reaction was cooled to room