Synthesis of [1,2,4,5]tetrazino[6′,1′:2,3]imidazo[4,5-c] isoquinolin-5-ones by microwave-assisted three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2011.07.129

An efficient and original Ugi multicomponent reaction of aminopyridines and aminopyrimidines is reported. Starting from aminotetrazine 6 or 7, an isocyanide and an ortho-carboxybenzaldehyde, tetrazinoimidazoisoquinolinones were isolated, after few minutes

Full text of DOI:10.1016/j.tetlet.2011.07.129

Tetrahedron Letters 52 (2011) 5224–5228
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of [1,2,4,5]tetrazino[60,10:2,3]imidazo[4,5-c]isoquinolin-5-ones by
microwave-assisted three-component reaction
Laurent Pellegatti a, Emeline Vedrenne a, Marie-Aude Hiebel a, Frédéric Buron a, Stéphane Massip b,
Jean-Michel Leger b, Christian Jarry b, Sylvain Routier a,
⇑
a Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 6005, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
b EA 4138, Pharmacochimie, Université Victor Segalen Bordeaux II, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and original Ugi multicomponent reaction of aminopyridines and aminopyrimidines is
reported. Starting from aminotetrazine 6 or 7, an isocyanide and an ortho-carboxybenzaldehyde, tetraz-
inoimidazoisoquinolinones were isolated, after few minutes of microwave irradiation, in good to excel-
lent yields. The scope of this method was extended by using different isocyanides.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 21 June 2011
Revised 15 July 2011
Accepted 27 July 2011
Available online 10 August 2011
Keywords:
Multicomponent reaction
Ugi reaction
Isocyanide
Heterocycle
Microwave irradiation
In the last decades, multicomponent reactions (MCR) have
emerged as a powerful tool for the synthesis of complex scaffolds.1
Isocyanide based MCRs are frequently exploited because of the
special reactivity of this functional group. Among them, the most
famous reactions are the Passerini,2 Ugi,2a,3 and recently the Gro-
ebke–Blackburn 3-component reactions,4 which affords imi-
dazo[1,2,a] annulated heterobicyclic compounds. This type of
structure is found in compounds showing a wide range of biologi-
O
O
R2
R1
N
N
N
N
HO
O
N C
3
R2
R1
N
N
N
N
NH2
+
N
N
Ugi cyclization
N
1
2
4 or 5
Scheme 1. Multicomponent synthesis.
O
O
N
N
N
N
N
cat (5%)
Solvent, MW
T °C, 10 min
N
HO
O
N
N
N
N
NH2
+
N
N
N
6
2
4a
N
C
3a
Scheme 2. Preparation of 4a.
⇑
Corresponding author. Tel.: +33(0) 238494853; fax: +33(0) 238417281.
E-mail address: sylvain.routier@univ-orleans.fr (S. Routier).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.129

L. Pellegatti et al. / Tetrahedron Letters 52 (2011) 5224–5228
5225
cal activities such as antiulcer,5 hypnotic,6 anxiolytic,7 and many
other biological activities.8 Indeed, new isocyanide based MCRs
are frequently published, allowing several degrees of structural
diversity.9
Table 1
Optimization of the conditions for the formation of 4a
Entry
Solvent
Heat
Catalyst
Yielda
1
2
3
4
5
6
7
8
9
10
MeOH
EtOH
i-PrOH
H2O
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
MW, 120 °C, 10 min
MW, 120 °C, 10 min
MW, 120 °C, 10 min
MW, 100 °C, 10 min
MW, 100 °C, 10 min
RT
—
—
—
—
—
—
—
25%
38%
62%
70%
76%
Traces
10%
60%
Traces
Traces
The well-known Ugi four-component condensation between
aldehydes, isocyanides, amines and carboxylic acids generally af-
fords N-substituted
a
-acylamino carboxamides.10 Lactams were
also obtained by using bifunctional reagents.11 Recently following
this strategy, Beifuss synthesized new pyrido[20,10:2,3]imi-
110 °C
dazo[4,5-c]isoquinolin-(6H)-one skeletons by
a microwave-as-
MW, 100 °C, 10 min
MW, 100 °C, 10 min
MW, 100 °C, 10 min
NH4Cl
Sc(OTf)3
TsOH
sisted three-component reaction using 2-aminopyridine, 2-
carboxybenzaldehyde and an isocyanide.11a
a
Based on the interests of our group in the synthesis of function-
alized imidazo[1,2-b][1,2,4,5]tetrazines,12 we disclose herein a
Yields are given for isolated product; MW: microwave irradiations; RT room
temperature.
O
O
R
N
N
N
N
N
N
HO
O
R
N C
N
N
N
3a-h
N
N
N
NH2
Toluene, MW
100 °C, 10 min
+
N
N
6
2
4a-h
Scheme 3. Variation of the isocyanide.
Table 2
Synthesis of compounds 4a–g
Entry
Isocyanides
Products
Yieldsa
76%
O
N
1
c-Hexyl isocyanide 3a
N
N
N
N
N
N
N
N
4a
O
N
2
n-Butyl isocyanide 3b
81%
N
N
N
N
N
N
4b
O
N
3
4
2-Pentyl isocyanide 3c
Traces
N
N
N
N
N
N
N
N
N
4c
O
HN
N
N
N
t-Butyl isocyanide 3d
61%
N
N
4d
O
N
O
N
5
2-Morpholinoethyl isocyanide 3e
68%
N
N
N
N
N
N
N
4e
(continued on next page)

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L. Pellegatti et al. / Tetrahedron Letters 52 (2011) 5224–5228
Table 2 (continued)
Entry
Isocyanides
Products
Yieldsa
O
N
6
Benzyl isocyanide 3f
71%
N
N
N
N
N
N
N
4f
O
O
O
N
7
p-Methoxyphenyl isocyanide 3g
62%
71%
N
N
N
N
N
N
N
N
N
N
N
4g
HN
N
N
8
Trimethylsilyl cyanide 3h
N
4d
a
Yields are given for isolated product.
new use of substituted amino[1,2,4,5]tetrazines 1 in the modified
Ugi multicomponent reaction (Scheme 1).
Table 3
Synthesis of compounds 5a–g
First, we started using an equimolar amount of aminotetrazine
6, 2-carboxybenzaldehyde 2 and cyclohexyl isocyanide 3 in meth-
anol (Scheme 2). The resulting mixture was irradiated at 120 °C for
10 min, which afforded the desired functionalized imidazo[1,2-
b][1,2,4,5]tetrazine in 25% yield (Table 1, entry 1). The replacement
of methanol by ethanol (Table 1, entry 2) and then by iso-propanol
(Table 1, entry 3) allowed us to improve the yield, affording the
imidazotetrazine 4a in 38% and 62% yield, respectively.
Compound 4a was finally isolated in 70% yield using water as
solvent, and in 76% yield with toluene (Table 1, entries 4 and 5).
As the best result was obtained with toluene, which is known for
its poor microwave absorbability, we thought that thermal condi-
tions should be tested. However, these conditions were less effi-
cient (Table 1, entries 6 and 7); that is, at room temperature, the
starting material was recovered and in refluxing toluene, the de-
sired product 4a was isolated in low yield. Consequently, micro-
wave irradiations and toluene as solvent were thus chosen for
the rest of the study. Then, the use of different additives was then
investigated. A dramatic decrease in yield was observed either
with ammonium chloride (Table 1, entry 8),13 or surprisingly, scan-
dium triflate.4 Moreover, p-toluene sulfonic acid14 totally inhibited
the reaction (Table 1, entries 9 and 10).
Entry Isocyanides
Products
Yieldsa
61%
O
N
N
N
Cl
Cl
1
c-Hexyl isocyanide 3a
N
N
N
5a
O
N
2
n-Butyl isocyanide 3b
79%
N
N
N
N
N
5b
O
O
N
3
4
5
2-Pentyl isocyanide 3c
53%
Cl
Cl
N
N
N
N
N
N
N
5c
The variation of the isocyanide partner 3 was then studied
(Scheme 3, Table 2).
HN
Alkyl isocyanides generally gave good results (Table 2), except
in the case of 2-pentyl isocyanide (Table 2, entry 3), which only
led to traces of expected product and mostly to the starting mate-
rials. Surprisingly, in the case of tert-butyl isocyanide, only com-
pound 4d was isolated in 61%, proving the relative lability of the
tert-butyl group without acidic treatment (Table 2, entry 4).14
Noteworthy, 4d can also be synthesized using trimethylsilyl cya-
nide as starting material (Table 2, entry 8).15 More functionalized
isocyanides can also be employed, as 2-morpholinoethyl isocya-
nide affords compound 4e in 68% yield (Table 2, entry 5). Finally,
benzyl and 4-methoxyphenyl isocyanides proved to be good part-
ners for the reaction, as compounds 4f and 4g were obtained in
71% and 62% yield, respectively (Table 2, entries 6 and 7).
N
N
t-Butyl isocyanide 3d
57%
N
5d
O
N
O
2-Morpholinoethyl isocyanide
3e
N
Traces
Cl
N
N
N
N
N
5e

L. Pellegatti et al. / Tetrahedron Letters 52 (2011) 5224–5228
5227
Table 3 (continued)
Entry Isocyanides
Products
Yieldsa
O
N
6
Benzyl isocyanide 3f
66%
Cl
N
N
N
N
N
5f
O
O
p-Methoxyphenyl isocyanide
3g
N
7
8
Traces
N
N
Cl
Cl
N
N
N
N
N
5g
O
HN
N
N
Figure 1. ORTEP diagram derived from the single-crystal X-ray analysis of
compound 5a.
Trimethylsilyl cyanide 3h
Traces
N
5d
Acknowledgment
a
Yields are given for isolated product.
We thank the Cancéropôle Grand Ouest, the Ligue Contre le
Cancer du Grand Ouest and the Region Centre (CrikMapAkt pro-
gram) for the financial support.
Next, we tried to introduce a chlorine atom on the scaffold,
which could allow coupling reactions at a later stage. Hence, 6-
chloro-1,2,4,5-tetrazin-3-amine 7 was employed as starting mate-
rial.16 The same behavior as pyrazolo derivative 6 was generally
observed with the different isocyanides (Table 3, Scheme 4). How-
ever, this amine did not lead to degradation with 2-pentyl isocya-
nide and compound 5c was isolated in 53% yield (Table 3, entry 3).
Decomposition was nevertheless noticed with 2-morpholinoethyl,
p-methoxyphenyl isocyanides and trimethylsilyl cyanide (Table 3,
entries 5, 7, and 8), as only traces of the desired compounds were
obtained.18
The structure of 5a was confirmed using X-ray diffraction. (
Fig. 1).17 Two independent molecules were found in the cell unit.
They only differ from the torsion angle between the cyclohexyl
ring and the hetero-polycyclic moiety, that is, molecule I: C(12)–
N(11)–C(20)–C(21) = ꢀ52.6(4)°, molecule II: C(62)–N(61)–C(70)–
C(71) = ꢀ52.6(4)°. The polycyclic skeleton adopts an almost planar
conformation, with, for example, dihedral angles C(12)–N(11)–
C(8)–N(6) = ꢀ171.8(3)°, C(14)–C(9)–N(10)–C(5) = ꢀ177.5(3)°. The
bond lengths C(8)–N(11), C(8)–C(9) and C(8)–N(6) and the dihedral
angle N(6)–C(8)–N(11)–C(20) = 13.4(5)°, illustrate the sp2 charac-
ter of C(8) and N(11), respectively.
References and notes
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In this Letter, we have shown that the modified Ugi multicom-
ponent reaction can be generalized to the use of amino[1,2,4,
5]tetrazines. The desired [1,2,4,5]tetrazino [60,10:2,3]imidazo[4,5-
c]isoquinolin-5-ones were generally isolated in good to excellent
yield. Studies on the functionalization of the 3-chloro-imi-
dazo[1,2-b][1,2,4,5]tetrazine derivatives are currently in progress
and results will be published in due course.
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O
O
R
Cl
N
N
N
N
HO
O
N
N
Cl
R
N C 3a-h
N
N
NH2
Toluene, MW
100 °C, 10 min
+
N
N
7
2
5a-h
Scheme 4. Preparation of compounds 5.

5228
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c = 17.1546 (1) Å,
group: P1, Z = 2, d = 1.469 g cmꢀ3
reflections were measured with final R = 6.57% (I > 2
collected with a R-axis Rapid Rigaku MSC diffractometer using the CuK
a
= 76.823 (5)°, b = 80.221 (4)°,
(Cu,
) = 2.274 mmꢀ1
(I)). All the data were
c
= 89.914 (6)°. Space
,
l
K
a
.
5688 Unique
r
a
radiation and a graphite monochromator. The structure was solved by direct
methods Shelx 86 and refined using Shelx 97 suite of programs.a,b The program
PLATONc was used for analysis and drawing figures. The positions of the H
atoms were deduced from coordinates of the non-H atoms and confirmed by
Fourier synthesis. The non-H atoms were refined with anisotropic temperature
parameters. H atoms were included for structure factor calculations but not
refined. CCDC 805069 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge at www.ccdc.cam.uk/
conts/retrieving.html (or from Cambridge Crystallographic Data Centre,
University Chemical Lab, 12 Union Road, Cambridge, CB2 1EZ, U.K.; e-mail:
deposit@ccdc.cam.ac.uk.) (a) Sheldrick, G. M.; Kröger, C.; Goddard, R. SHELX 86
in Crystallographic Computing 3; Oxford University Press: New York, 1985. pp
175–189; (b) Sheldrick, G. M. SHELX 97, Program for the Refinement of the Crystal
Structures; University of Göttingen: Germany, 1997; (c) Spek, A. L. Acta
Crystallogr., Sect. A 1990, 46, 34.
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8355–8357.
16. For the synthesis of compound 1, see: (a) Li, Y.; Asadi, A.; Perrin, D. M. J. Fluor.
Chem. 2009, 130, 377–382; For the synthesis of compound 2, see: (b) Kerth, J.;
Löbbecke, S. Propell. Explos. Pyrot. 2002, 27, 111–118; (c) Coburn, M. D.;
Buntain, G. A.; Harris, B. W.; Hiskey, M. A.; Lee, K. Y.; Ott, D. G. J. Heterocycl.
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18. General procedure: A 2–5 mL microwave vial was charged with the appropriate
aminotetrazine (1.0 equiv), 2-carboxybenzaldehyde (1.0 equiv) and isocyanide
(1.0 equiv) in toluene. The resulting solution was subjected to microwave
irradiations at 100 °C for 10 min. The mixture was then filtered and the desired
compound was isolated without further purification as an orange solid.
17. Crystallographic study: The structure of compound 12 has been established by
X-ray crystallography (Fig. 1). Single red crystals of 12 were obtained by slow