An efficient synthesis of novel heterocycle-fused derivatives of 1-oxo-1,2,3,4-tetrahydropyrazine using Ugi condensation

Article abstract of DOI:10.1016/j.tetlet.2004.11.168

We present a convenient synthesis of novel pyrrole- and indole-fused 1-oxo-1,2,3,4-tetrahydropyrazine heterocyclic structures using a novel modification of four-component Ugi condensation. We demonstrate the usefulness and versatility of the developed approach for the synthesis of variously substituted compounds, and discuss the scope and limitations of the chemistry involved.

Full text of DOI:10.1016/j.tetlet.2004.11.168

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 881–884
An efficient synthesis of novel heterocycle-fused derivatives of
1-oxo-1,2,3,4-tetrahydropyrazine using Ugi condensation
Alexey P. Ilyn,a Julia A. Kuzovkova,a Victor V. Potapov,a Alexandre M. Shkirando,a
Denis I. Kovrigin,a Sergey E. Tkachenkob and Alexandre V. Ivachtchenkob,*
aDepartment of Organic Chemistry, Chemical Diversity Research Institute, 114401 Khimki, Moscow Reg., Russia
bChemDiv, Inc., 11558 Sorrento Valley Rd., Suite 5, San Diego, CA, 92121, USA
Received 13 October 2004; revised 11 November 2004; accepted 16 November 2004
Available online 21 December 2004
Abstract—We present a convenient synthesis of novel pyrrole- and indole-fused 1-oxo-1,2,3,4-tetrahydropyrazine heterocyclic struc-
tures using a novel modification of four-component Ugi condensation. We demonstrate the usefulness and versatility of the developed
approach for the synthesis of variously substituted compounds, and discuss the scope and limitations of the chemistry involved.
Ó 2004 Elsevier Ltd. All rights reserved.
3,4-Dihydropyrrolo[1,2-a]pyrazin-1(2H)-one fragment
is present in a wide number of natural and synthetic bio-
logically active agents. Among them are antineoplastic
and antibacterial alkaloids longamide, longamide B,
and phakellstatins isolated from marine organisms as
well as their synthetic analogs,1 antitrombotic agents,2
potential antiprotozoal drugs,3 and the insect feeding
deterrents.4 Aryl-fused analogs of 3,4-dihydropyr-
rolo[1,2-a]pyrazin-1(2H)-ones, such as pyrazino[1,2-
a]indoles, represent another group of compounds with
interesting but still relatively little explored pharmaceu-
tical properties described in a number of recent patent
applications.5 According to these examples, hetero-
cycle-fused derivatives of 1-oxo-1,2,3,4-tetrahydro-
pyrazine represent promising synthetic targets.
Development of efficient synthetic approaches to the
related scaffolds will provide a valuable source of novel
physiologically active agents. In this paper, we commu-
nicate our success in developing a novel four-component
Ugi-type reaction for the synthesis of novel 3-carbox-
amide derivatives of 3,4-dihydropyrazino[1,2-a]indol-
1(2H)-one and 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-
one, which can be readily applied in combinatorial
chemistry approaches.
In most of the reported synthetic approaches to pyrrole-
and indole-fused 1-oxo-1,2,3,4-tetrahydropyrazines, key
reaction is the intermolecular cyclization of the appro-
priate pyrrole- or indole-2-carboxylic acid derivatives
leading to the desired heterocycles. For example, substi-
tuted pyrazino[1,2-a]indole-1-ones were obtained from
the corresponding 1H-indole-2-carboxylic acid allyl
amides6 or 1H-indole-2-carboxylates.7 However, the de-
scribed synthetic strategies have found limitations
mainly due to lack of versatility and a limited number
of the appropriate initial reactants.
Recently, Ugi reaction was shown to be an effective ap-
proach to the assembly of differently substituted pyra-
zines.8 One of important modifications of the classical
four-component Ugi reaction includes the use of bifunc-
tional reagents. Thus, modified versions of the Ugi four-
component reaction using bifunctional aldehyde or keto
acids, amine, and isocyanide as starting materials, have
been reported.9 In this work, we show first examples of a
novel modification of the four-component Ugi reaction
between isonitrile, amine, and a bifunctional azahetero-
cyclic reagent bearing a (2-oxoethyl)aminoacetic acid
fragment. To illustrate our approach, we describe here
the synthesis of a medium sized library of novel 1-oxo-
1,2,3,4-tetrahydropyrazino[1,2-a]indoles 6{1–98} and
1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]pyrroles 6{99–
141} (Scheme 1).
Keywords: Ugi condensation; 3,4-Dihydropyrazino[1,2-a]indol-1(2H)-
one; 3,4-Dihydropyrrolo[1,2-a]pyrazin-1(2H)-one; Library.
*
Key bifunctional reagents used in the four-component
reaction were obtained from 2-pyrrole-2-carboxylates
Corresponding author. Tel.: +1 858 794 4860; fax: +1 858 794
4931; e-mail addresses: dk@chemdiv.com; av@chemdiv.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.168

882
A. P. Ilyn et al. / Tetrahedron Letters 46 (2005) 881–884
R3
O
O
R3
O
R4-NC 4a-g
R3
MeCOCH2Cl
K2CO3, 18-crown-6
R5
R5-NH2 5a-i
R
CH3
O
N
O
R2
CH3
R2
R2
O
MeOH
40 oC, 4-18h
1,4-dioxane, reflux, 5h
N
O
N
NH
R1
R1
6{1-141}, 45-96%
R1
CH3
HN
R4
1a-i
R = CH3: 2a-i, 60-85%
R = H: 3a-i, 75-95%
2% NaOH,* H2O
°
70 C, 6h
Scheme 1. Synthesis of 3-carboxamide derivatives of 3,4-dihydropyrazino[1,2-a]indol-1-(2H)-one 6{1–98} and 3,4-dihydropyrrolo[1,2-a]pyrazin-
1(2H)-one 6{99–141}. *1% NaOH in the case of compound 2i (R1 = R3 = CH3, R2 = COOMe).
1a–i, which were available from commercial sources or
prepared as reported.10,11 A solution of carboxylate
1a–i in 1,4-dioxane was treated with chloroacetone un-
der phase transfer conditions, in the presence of
K2CO3 and 18-crown-6, to afford the desired product
2a–i in a good yield (60–85%). Mild alkali hydrolysis
of 2a–i led to keto acids 3a–i (yield 75–95%). Then we
have found that the reaction of keto acids 3a–i with iso-
nitriles 4a–g and amines 5a–i led to the corresponding 3-
carboxamide derivatives 6{1–141}, which were not pre-
viously described in literature. The reaction smoothly
proceeded in methanol at 40 °C to yield the desired
products in 45–96% yield.12 The reaction presumably
follows the same initial course as the classical Ugi con-
densation13 with an intermediate imine being attacked
by the isonitrile to give a nitrilium intermediate, which
then undergoes intramolecular cyclization.
derivatives could be used. With respect to amine compo-
nent, various aliphatic and aromatic primary amines,
such as substituted anilines, linear, and branched ali-
phatic amines and nitrogen-containing compounds,
were tolerated without any limitations. A restriction is
the limited number of commercially or synthetically
available isonitriles. In this work, we used seven different
isonitriles 4a–g available from ChemDiv.
Structures and yields of some representative compounds
are shown in Tables 1 and 2. Isolated yields of 6{1–141}
were generally high (>60%, up to 96%), except for a few
cases. All compounds were obtained as racemic mixtures
of enantiomers. The assignment of these structures was
made on the basis of 1H NMR, 13C NMR, and high-res-
olution mass-spectroscopy data.14 The nonequivalent
methylene protons of the pyrazinone ring are sometimes
concealed by other signals, but usually can be seen as
doublets in the range of d 3.90–5.50 ppm with the gem-
inal spin–spin coupling constants in the range of 5.6–
8.2 Hz. In many cases, pure crystalline substances could
be obtained, thus allowing firm relative and absolute ste-
reochemical assignments to be made to the individual
compounds through X-ray crystallography. Single crys-
As a synthetic tool for creating diverse compound
libraries, the developed Ugi-type condensation offers
a large number of potential input reactants (Fig. 1).
We have observed that the nature of R1–R3 substituents
does not substantially affect the reaction yield and time,
and several differently substituted pyrrolo-2-carboxylate
CH3
R3
O
N
NH
R2
R2
R2
R2
O
O
O
O
O
O
1
N
O
CH3
N
H
N
H
O CH3
R
CH3
N
CH3
R1
H
H
1h: R1 = 2-furyl, R2 = R3 = H
1i: R1 = R3 = Me, R2 = CO2Me
1f: R2 = Me
1d: R2 = F
1a: R1 = R2 = H
1g: R2 = MeO
1e: R2 = MeO
1b: R1 = 6-MeO, R2 = H
1c: R1 = 7-MeO, R2 = 4-MeO
CH3
NC
NC
NC
H3C
NC
NC
CH3
NC
H3C
NC
O
H3C
4a
4b
4c
4d
4e
4f
4g
CH3
CH3
N
CH3
H3C
H3C
NH2
O
NH2
H3C
NH2
H3C
NH2
5a
5b
5c
5d
NH2
NH2
NH2
NH2
NH2
S
F
Cl
Cl
N
5e
Figure 1. Evaluated building blocks.
5f
5g
5h
5i

A. P. Ilyn et al. / Tetrahedron Letters 46 (2005) 881–884
883
Table 1. Structures and yields of representative 3,4-dihydropyrazino[1,2-a]indol-1(2H)-ones
R3
O
R5
N
R2
CH3
N
O
HN
R4
R1
No
R1
H
R2
H
R3
H
R4
R5
Yield, %
85
HRMS, exp.
443.2238
HRMS, calcd
6{1}
434.2238
F
*
*
*
6{2}
6{3}
7-MeO
H
H
H
H
92
80
449.2185
447.0321
449.2183
447.0316
*
O
N
H3C
*
1-Pyrrolyl
*
H3C
H3C
H3C
*
6{4}
6{5}
H
H
8-F
AcNH
AcNH
78
81
485.2009
483.2958
485.2017
483.2966
*
S
H3C
8-CH3O
*
*
H3C
6{6}
6{7}
H
H
8-CH3
1-Pyrrolyl
1-Pyrrolyl
64
68
565.2334
507.2976
565.2341
507.2966
H3C
*
*
Cl
*
8-CH3O
*
H3C
H3C
O
*
N
6{8}
6-MeO
9-MeO
H
83
443.265
443.2653
*
H3C
Table 2. Structures and yields of representative 3,4-dihydropyrazino[1,2-a]pyrazin-1(2H)-ones (6-(2-furyl) derivatives)
O
R5
N
CH3
N
O
O
HN
R4
No
R4
R5
Yield, %
89
HRMS, exp.
454.1891
HRMS, calcd
454.18912
H3C
6{99}
Cl
*
H3C
*
6{100}
6{101}
6{102}
6{103}
6{104}
78
85
62
81
68
433.0321
455.2650
426.1142
452.2010
441.2863
433.0317
455.2653
426.1147
452.2002
441.286
*
*
N
O
N
*
*
H3C
*
*
H3C
CH3
*
*
S
H3C
N
*
H3C
O
*
H3C
H3C
N
6{105}
64
443.5761
443.5758
*
*

884
A. P. Ilyn et al. / Tetrahedron Letters 46 (2005) 881–884
7. Guandalini, L.; Martini, E.; Gualtieri, F.; Romanelli, M.
N.; Varani, K. ARKIVOC 2004, V, 286–300.
tals of compounds suitable for X-ray analysis were
grown from diethyl ether.
8. (a) Cheng, J.-F.; Chen, M.; Arrhenius, T.; Nadzan, A.
Tetrahedron Lett. 2002, 43, 6293–6295; (b) Rossen, K.;
Sager, J.; DiMichele, L. M. Tetrahedron Lett. 1997, 38,
3183–3186; (c) Illgen, K.; Nerdinger, S.; Fuchs, T.;
Friedrich, C.; Weber, L.; Herdtweck, E. Synlett 2004, 1,
53–56.
9. (a) Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. J.
Org. Chem. 1999, 64, 1074–1076; (b) Marcacchini, S.;
Pepino, R.; Torroba, T.; Miguel, D.; Garcia-Valverde, M.
Tetrahedron Lett. 2002, 43, 8591–8593.
In summary, we have developed a novel synthetic ap-
proach to the assembly of the pyrrolo- and indole[1,2-
a]pyrazin-1-one heterocycles based on a novel modifica-
tion of the Ugi four-component reaction. A distinctive
feature of our synthetic method is the use of bifunctional
azaheterocyclic reagents bearing a (2-oxoethyl)amino-
acetic acid fragment. Due to a wide spectrum of such re-
agents available, this reaction opens wide possibilities
for synthesis of novel or poorly studied annelated het-
erocyclic systems such as 1-oxo-1,2,3,4-tetrahydropyr-
rolo[1,2-a]pyrazine-3-carboxamide as well as other
heterocyclic scaffolds, which were not previously de-
scribed in literature.
10. Knight, D. W.; Redfern, A. L.; Gilmore, J. Synlett 1998, 7,
731–732.
11. Hudkins, R. L. Heterocycles 1995, 5, 1045–1049.
12. General procedure for preparation of compounds 6{1–
141}. The equimolar amounts of keto acid 3, the isonitrile
4, and the amine 5 were dissolved in methanol to an
approximate concentration of 1 M in each component.
The reaction mixture was stirred at 40 °C for 4–18 h. The
reaction was followed by TLC (5% MeOH in CH2Cl2). On
completion, the reaction mixture was cooled to rt, the
formed precipitate was filtered out and purified (if desired)
by recrystallization from diethyl ether of by chromato-
graphy on silica gel, eluting with a gradient of 0–10%
MeOH in CH2Cl2.
13. (a) Ugi, I. Isonitrile Chemistry; Academic: London, 1971;
(b) For reviews see: Armstrong, R. W.; Brown, D. S.;
Keating, T. A.; Tempest, P. A. In Combinatorial Chem-
istry Synthesis and Application; Wilson, S., Czarnik, A.
W., Eds.; John Wiley and Sons: New York, 1997; p 153;
(c) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.;
Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29,
123–131.
Acknowledgements
The authors would like thank Dr. Michail Yu. Antipin
for solving the X-ray structures. The authors would also
like thank Dr. Konstantin V. Balakin for help in prepa-
ration of the manuscript.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet-
let.2004.11.168. Spectral data for representative novel
compounds and crystallographic data for compounds
6{3} and 6{105} is available. The supplementary data
is available online with the paper in ScienceDirect.
14. Analytical spectral data for representative compounds 6.
1
Compound 6{5}: H NMR (DMSO + CCl4, 400 MHz) d
1.2–1.8 (m, 14H, cyclooctane), 1.5 (s, 9H, 3CH3), 2.2 (s,
3H, CH3), 3.2–3.33 (m, 1H, CH), 2.8 (s, 3H, CH3), 2.85–
2.96 (m, 1H, CH), 6.89 (d, 1H, J = 7.0 Hz, ArH), 7.21 (d,
1H, J = 7.0 Hz, ArH), 7.62 (s, 1H, ArH), 7.9–8.0 (m, 1H,
NH), 9.8 (s, 1H, NCO); 13C NMR (100 MHz, DMSO) d
21.4, 21.5, 21.7, 24.0, 24.1, 25.7, 27.2, 27.6, 31.8, 31.9, 49.9,
50.3, 51.2, 55.9, 64.8, 67.0, 104.9, 111.9, 116.5, 116.6,
128.2, 120.3, 130.3, 132.0, 169.1; HRMS m/z 483.2958
(M+). Compound 6{7}: 1H NMR (DMSO + CCl4,
400 MHz) d 1.1–2.0 (m, 14H, cycloheptane, CH2), 1.6 (s,
3H, CH3), 3.22 (s, 3H, CH3), 3.26–3.48 (m, 3H, CH2), 3.6–
3.71 (m, 1H, CH), 3.72–3.8 (m, 1H, CH2), 3.73 (s, 3H,
CH3), 4.0 (d, 1H, J = 5.4 Hz, CH2), 4.83 (d, 1H,
J = 5.4 Hz, CH2), 6.16–6.19 (t, 2H, J = 1.2 Hz, ArH),
6.88 (d, 1H, J = 2.4 Hz, ArH), 6.91 (d, 1H, J = 2.8 Hz,
ArH), 6.96 (d, 1H, J = 3.2 Hz, ArH), 6.98 (s, 1H, ArH),
7.35 (d, 1H, J = 7.4 Hz, ArH), 7.45 (d, 1H, J = 7.6 Hz,
NH); 13C NMR (100 MHz, DMSO) d 20.6, 23.7, 23.8,
27.7, 29.5, 33.9, 34.0, 49.6, 50.6, 52.5, 54.6, 55.4, 57.9, 59.7,
70.2, 70.3, 99.4, 108.1, 109.3, 111.6, 112.2, 119.6, 119.9,
123.0, 123.1, 128.6, 129.6, 154.7, 159.2; HRMS m/z
References and notes
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1
507.2976 (M+). Compound 6{99} : H NMR (DMSO +
CCl4, 400 MHz) d 0.7 (t, 3H, J = 8.2 Hz, CH3), 1.0–1.13
(q, 2H, J = 8.3 Hz, CH2), 1.15–1.2 (m, 1H, CH), 1.48 (s,
1H, CH), 2.97–3.11 (q, 2H, J = 7.8 Hz, CH2), 3.95–4.2 (d,
d, 2H, J = 7.4 Hz, CH2), 4.9–5.0 (d, 1H, J = 7.5 Hz, CH2),
5.33–5.49 (d, 1H, J = 7.5 Hz, CH2) 6.4 (d, 1H, J = 8.2 Hz,
ArH), 6.47 (2d, 1H, J = 8.4Hz, ArH), 6.52 (d, 1H,
J = 8.1 Hz, ArH), 6.74 (d, 1H, J = 8.1 Hz, ArH), 7.2–
7.36 (m, 4H, ArH), 7.6 (d, 1H, J = 8.2 Hz, ArH); HRMS
m/z 454.1891 (M+).
6. Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. J. Org.
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