Streamlined access to 2,3-dihydropyrazino[1,2-a]indole-1,4-diones via Ugi reaction followed by microwave-assisted cyclization

Article abstract of DOI:10.1016/j.tetlet.2009.07.096

An efficient method is developed to construct drug-like 2,3-dihydropyrazino[1,2-a]indole-1,4-diones from 1H-indole-2-carboxylic acids, ethyl pyruvate, isocyanides, and primary amines via a one-pot, two-step procedure involving Ugi reaction and microwave-a

Full text of DOI:10.1016/j.tetlet.2009.07.096

Tetrahedron Letters 50 (2009) 5529–5531
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Streamlined access to 2,3-dihydropyrazino[1,2-a]indole-1,4-diones via Ugi
reaction followed by microwave-assisted cyclization
Sergey Tsirulnikov a, Mikhail Nikulnikov a, Volodymyr Kysil b, Alexandre Ivachtchenko b, Mikhail Krasavin a,
*
a Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg. 141400, Russia
b ChemDiv, Inc., 6605 Nancy Ridge Dr., San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method is developed to construct drug-like 2,3-dihydropyrazino[1,2-a]indole-1,4-diones
from 1H-indole-2-carboxylic acids, ethyl pyruvate, isocyanides, and primary amines via a one-pot,
two-step procedure involving Ugi reaction and microwave-assisted cyclization.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 7 June 2009
Revised 10 July 2009
Accepted 17 July 2009
Available online 22 July 2009
Keywords:
Isocyanide-based multi-component
reactions
Post-Ugi modifications
Microwave-assisted synthesis
Combinatorial chemistry
The Ugi multi-component reaction (U-MCR)1 is an efficient pro-
cedure for coupling reaction components from four different func-
tional classes in a single condensation product. While it may have
initially seemed that such striking atom economy would be tar-
nished by the redundancy of dipeptoid motifs present in the prod-
ucts of the U-MCR, the potential of the latter as a source of almost
infinite scaffold diversity is uncovered by intelligent design of
post-Ugi events. From the earlier work of Hulme on the ‘Ugi-depro-
tect-cyclize’ (UDC) strategy2 to skillful functionalization of the U-
MCR product with appendages capable of reacting in a second,
orthogonal event (such as Mitsbunobu,3 Heck,4 Diels–Alder,5 or
photocycloaddition6 processes)—it has become clear that U-MCR
can be utilized for the formation of a wide range of heterocyclic
molecular frameworks. Numerous reports on post-Ugi chemistry
in the last decade (thoroughly reviewed by Akritopoulou-Zanze7)
have promoted further activity in this area as witnessed in the re-
cent literature.8
our later finding that other isocyanide-derived amide termini in
scaffolds such as 1 can also cyclize onto the pyrazole moiety (albeit
less effectively) and that replacement of the pyrazole with less
reactive indole leads to significantly diminished yields.10
Herein we report that the products 3 of U-MCR of 1H-indole-2-
carboxylic acids and ethyl pyruvate with various amines and isocy-
anides undergo high yielding microwave-assisted cyclization into
2,3-dihydropyrazino[1,2-a]indole-1,4-diones 4 (Scheme 2). Com-
pounds containing such motifs have been reported to possess cyto-
toxic,11 melatoninergic,12 antiviral13, and antifungal14 activities.
This broad medicinal relevance and the constrained peptidomi-
metic character of 4 make these new compounds attractive addi-
tions to any diversity set for biological screening.
The cyclization precursors 3 were prepared on 3 mmol scale as
follows: Equimolar amounts of the amine and ethyl pyruvate were
dissolved in methanol (10 mL) in a microwave reactor tube and
heated at 50 °C for one hour to ensure complete imine formation.
We recently reported that the products 1 of U-MCR of 1H-pyr-
azole-3-carboxylic acids in combination with tert-butyl isocyanide
undergo microwave-assisted cyclization giving rise to medic-
inally important 5,6-dihydropyrazolo[1,5-a]pyrazine-4,7-diones 2
(Scheme 1).9 In this cyclization process, the unsubstituted pyrazole
nitrogen acts as an internal nucleophile to displace tert-butylamine
from the terminal amide functionality. This view was supported by
R1
R1
O
O
N
R2
O
H
N
N
N
AcOH
N
R2
N
NH
R3
MW, 20 min, 180 oC
O
R3
1
2
* Corresponding author. Tel.: +7 495 995 4944; fax: +7 495 626 9780.
E-mail address: myk@chemdiv.com (M. Krasavin).
Scheme 1. Cyclization of Ugi reaction products 1 derived from t-BuNC and 5-
substituted-1H-pyrazole-3-carboxylic acids.9
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.096

5530
S. Tsirulnikov et al. / Tetrahedron Letters 50 (2009) 5529–5531
R1
HN
O
R3
OH
O
R1
O HN
MeOH
AcOH
R1
O
O
R3 N+
C
H2N R2
R2
N
+
N
50 oC to r.t., 24 h
MW, 30 min, 180 oC
N
N
H
R2
O
O
O
3
EtO
4
O
NH
R3
OEt
Scheme 2. Products of the Ugi reaction of 1H-indole-2-carboxylic acids, ethyl pyruvate, isocyanides, and primary amines and their microwave-assisted cyclization.
Next, a solution of the 1H-indole-2-carboxylic acid (1 equiv) in a
minimum amount of methanol was added followed by a solution
of the isocyanide (1 equiv) in methanol (1 mL). The mixture was
stirred at room temperature for 24 h, at which point the reaction
was complete by LC–MS analysis. The solvent was removed in va-
cuo15 and the resulting solid was re-dissolved in glacial acetic acid
(3 mL) and the reaction vessel sealed.
Microwave-assisted cyclization was achieved on heating the
above solution at 180 °C for 30 min using a Biotage InitiatorTM
microwave synthesizer operating at 100 W. Notably, incomplete
conversion was achieved in short reaction times or at lower tem-
peratures. However, only products corresponding to the loss of
an ethanol molecule were observed in the crude mixtures, with
complete absence of the products similar to 2 resulting from cycli-
zation onto the amide function. On cooling, the contents of the
tube were poured into water (25 mL), and the resulting dense pre-
cipitate was collected by filtration. For all 17 examples studied, this
procedure led to crude products of at least 85% purity (as deter-
mined by LC–MS). The products were obtained in good yields
and analytically pure form by column chromatography on silica
gel using an appropriate gradient of methanol in dichloromethane
(Table 1). The identities and purities of products 4a–q were con-
firmed by 1H and 13C NMR spectroscopy and by elemental
analyses.16
In conclusion, we have developed an efficient method to con-
struct drug-like 2,3-dihydropyrazino[1,2-a]indole-1,4-diones from
1H-indole-2-carboxylic acids, ethyl pyruvate, isocyanides, and pri-
mary amines via a one-pot, two-step procedure involving Ugi reac-
tion and post-Ugi microwave-assisted cyclization. This procedure
is amenable to parallel synthesis due to its simplicity and easy
purification of the products.
References and notes
1. Ugi, I.; Meyr, R.; Fitzer, U.; Steinbrucker, C. Angew. Chem. 1959, 71, 386–390.
2. (a) Hulme, C.; Cherrier, M.-P. Tetrahedron Lett. 1999, 40, 5295–5299; (b)
Tempest, P.; Ma, V.; Thomas, S.; Hua, Z.; Kelly, M. G.; Hulme, C. Tetrahedron Lett.
2001, 42, 4959–4962; (c) Tempest, P.; Pettus, L.; Gore, V.; Hulme, C. Tetrahedron
Lett. 2003, 44, 1947–1950.
3. Banfi, L.; Basso, A.; Guanti, G.; Lecinska, P.; Riva, R. Org. Biomol. Chem. 2006, 4,
4236–4240.
4. Umkehrer, M.; Kalinski, C.; Kolb, J.; Burdack, C. Tetrahedron Lett. 2006, 47,
3423–3426.
5. (a) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851–1854; (b) Ilyin, A.; Kysil, V.;
Krasavin, M.; Kurashvili, I.; Ivachtchenko, A. V. J. Org. Chem. 2006, 71, 9544–
9547.
6. (a) Akritopoulou-Zanze, I.; Whitehead, A.; Waters, J. E.; Henry, R. F.; Djuric, S.
W. Org. Lett. 2007, 9, 1299–1302; (b) Akritopoulou-Zanze, I.; Whitehead, A.;
Waters, J. E.; Henry, R. F.; Djuric, S. W. Tetrahedron Lett. 2007, 48, 3549–3552.
7. Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125–147.
8. (a) Wu, J.; Yong, J.; Wei-Min, D. Synlett 2009, 1162–1166; (b) Hulme, C.;
Chapetta, S.; Griffith, C.; Lee, Y.-S.; Dietrich, J. Tetrahedron Lett. 2009, 50, 1939–
1942; (c) Erb, W.; Neuville, L.; Zhu, J. J. Org. Chem. 2009, 74, 3109–3115; (d)
Basso, A.; Banfi, L.; Guanti, G.; Riva, R. Org. Biomol. Chem. 2009, 7, 253–258.
9. Nikulnikov, M.; Tsirulnikov, S.; Kysil, V.; Ivachtchenko, A.; Krasavin, M. Synlett
2009, 260–262.
Table 1
2,3-Dihydropyrazino[1,2-a]indole-1,4-diones 4 prepared in this work
O
R1
R2
N
N
10. Nikulnikov, M.; Krasavin, M. IV International Conference on Multi-Component
Reactions and Related Chemistry, 24–28 May, 2009, Ekaterinburg, Poster
Abstract 18.
11. Boger, D. L.; Fink, B. E.; Hedrick, M. P. Bioorg. Med. Chem. Lett. 2000, 10, 1019–
1020.
O
O
NH
R3
4a-q
12. Attia, M. I.; Witt-Enderby, P. A.; Julius, J. Bioorg. Med. Chem. 2008, 16, 7654–
7661.
Entry
Product
R1
R2
R3
Yield (%)
13. Sinha, S.; Srivastava, R.; De Clercq, E.; Singh, R. K. Nucleosides, Nucleotides,
Nucleic Acids 2004, 23, 1815–1824.
14. Houston, D. R.; Synstad, V. G.; Eijsink, V. G. H.; Stark, M. J. R.; Eggleston, I. M.;
Van Aalten, D. M. F. J. Med. Chem. 2004, 47, 5713–5720.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
6-MeO
5-Cl
6-MeO
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
H
Bn
Ph
Cyclohexyl
Cyclopentyl
4-MeC6H4CH2
4-FC6H4CH2
3-FC6H4CH2
Cycloheptyl
Cyclopentyl
Bn
45
54
72
68
62
47
73
38
68
41
44
58
67
36
43
48
55
4-MeC6H4CH2
4-iPrC6H4
4-iPrC6H4
4-iPrC6H4
Bn
15. Parallel evaporation of volatiles from the microwave reactor tube was carried
out using GeneVacÒ equipment.
16. Characterization data for selected compounds: compound 4a—white solid,
mp = 164–166 °C; 1H NMR (DMSO-d6, 300 MHz) d 8.05 (d, J = 7.6 Hz, 1H), 7.85
(d, J = 2.2 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.18–7.35 (m, 5H), 7.08
(dd, J = 8.8, 2.5 Hz, 1H), 4.81 and 4.32 (ABq, J = 16.2 Hz, 2H), 3.86 (s, 3H), 3.40
(m, 1H), 1.73 (s, 3H), 1.36–1.70 (m, 5H), 0.97–1.21 (m, 5H); 13C NMR (DMSO-d6,
75 Hz) d 165.2, 164.6, 159.8, 156.9, 137.9, 135.7, 128.1, 127.9, 127.1, 126.7,
123.5, 122.7, 114.7, 113.3, 99.6, 71.6, 55.7, 49.4, 46.6, 31.6, 31.4, 25.2, 24.7,
22.5; LC–MS (M+H+) 460; calcd for C27H29N3O4: C, 70.57; H, 6.36; N, 9.14;
found: C, 70.63; H, 6.42; N, 9.16. Compound 4d—beige solid, mp = 176 °C
(decomp.); 1H NMR (DMSO-d6, 300 MHz) d 8.68 (m, 1H), 8.32 (d, J = 8.9 Hz, 1H),
7.91 (m, 1H), 7.58 (dd, J = 8.6, 1.9 Hz, 1H), 7.45 (s, 1H), 7.21 (m, 4H), 7.05 (m,
4H), 4.27 (m, 2H), 2.95 (m, 1H), 1.76 (s, 3H), 1.25 (d, J = 6.9 Hz, 6H); 13C (DMSO-
d6, 75 Hz) d 167.1, 163.9, 161.4 (d, JC–F = 2.9 Hz), 156.6, 148.7, 135.0, 134.7,
2,3-Me2C6H4
Ph
Bn
Bn
2,5-Me2C6H4
2,4-Me2C6H4
3,4-Me2C6H4
3-MeSC6H4
4-iPrC6H4
4-iPrC6H4
2-MeC6H4CH2
Bn
Cyclopentyl
Bn
Cyclopentyl
MeOCH2CH2
Cyclopentyl
Cyclopentyl
Cyclohexyl

S. Tsirulnikov et al. / Tetrahedron Letters 50 (2009) 5529–5531
5531
133.0, 131.2, 130.6, 129.9, 129.5 (d, JC–F = 7.9 Hz), 129.4, 127.6, 126.7, 122.2,
117.3, 114.8 (d, JC–F = 21.1 Hz), 112.3, 72.2, 42.9, 33.0, 23.6, 21.1; LC–MS
(M+H+) 518; calcd for C29H25ClFN3O3: C, 67.24; H, 4.86; N, 8.11; found: C,
67.23; H, 4.91; N, 8.16. Compound 4n—white solid, mp = 148–150 °C; 1H NMR
(DMSO-d6, 300 MHz) d 8.49 (t, J = 5.5 Hz, 1H), 8.32 (d, J = 8.9 Hz, 1H), 7.94 (d,
J = 2.0 Hz, 1H), 7.60 (dd, J = 8.9, 2.0 Hz, 1H), 7.46 (s, 1H), 7.32 (d, J = 8.2 Hz, 2H),
7.14 (d, J = 8.2 Hz, 2H), 3.22 (s, 3H), 3.20–3.33 (m, 4H), 2.94 (m, 1H), 1.69 (s,
3H), 1.24 (d, J = 7.0 Hz, 6H); 13C (DMSO-d6, 75 Hz) d 167.0, 163.9, 156.6, 148.6,
134.9, 132.9, 131.1, 130.5, 129.7, 129.4, 127.6, 126.9, 122.2, 117.4, 112.3, 71.9,
69.8, 58.0, 33.1, 23.8, 21.2; LC–MS (M+H+) 468; calcd for C25H26ClN3O4: C,
64.17; H, 5.60; N, 8.98; found: C, 64.22; H, 5.66; N, 9.04.