A cascade reaction of azolopyrimidines. Synthesis of unusual indole and azaindole derivatives

Article abstract of DOI:10.1039/c2cc34539k

The reaction of bromo substituted pyrido[3′,2′:4,5]pyrrolo-[1, 2-c]pyrimidine and pyrimido[1,6-a]indole methyl carboxylates with primary amines is described. The expected amide formation occurs but it is followed by an unexpected cascade process involving attack of the amine to the pyrimidine ring, opening of the pyrimidine ring, loss of the bromine substituent and competitive cyclizations to afford unusual imidazolidene substituted indoles and azaindoles.

Full text of DOI:10.1039/c2cc34539k

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COMMUNICATION
A cascade reaction of azolopyrimidines. Synthesis of unusual indole and
azaindole derivativesw
a
a
a
b
Marıa Moron, Carolina Burgos,* Julio Alvarez-Builla, Antonio Salgado,
´
´
Marta E. G. Mosquerac and Juan J. Vaquero*a
Received 25th June 2012, Accepted 20th July 2012
DOI: 10.1039/c2cc34539k
The reaction of bromo substituted pyrido[30,20:4,5]pyrrolo-[1,2-c]-
pyrimidine and pyrimido[1,6-a]indole methyl carboxylates with
primary amines is described. The expected amide formation occurs
but it is followed by an unexpected cascade process involving attack
of the amine to the pyrimidine ring, opening of the pyrimidine ring,
loss of the bromine substituent and competitive cyclizations to
afford unusual imidazolidene substituted indoles and azaindoles.
The pyrrolo[1,2-c]pyrimidine system is a most interesting
indolizine analogue having an extra nitrogen heteroatom.1
This heterocyclic system, although rare in Nature, is found
in the marine alkaloid hinckdentine (1)2 and in the variolins,
a family of alkaloids isolated from the Antarctic sponge
Kirkpatrickia variolosa, which have antitumor and antiviral
activity (Fig. 1).3 These alkaloids, in particular variolin B (2),
have attracted the attention of several groups that have been
involved in their total syntheses.4
Scheme 1 Synthesis of the azaindole derivatives 6a/7a.
Our strategy for their synthesis involved the reaction of the
acid 3 or ester 4,6 with different amino acids or amines in order
to form the corresponding peptides or amides, respectively.
In the course of these works, we attempted the reaction of 4
with 2-methoxyethylamine. Yet this reaction did not afford the
expected amide derivative 5, but the unexpected azaindole
derivatives 6a and 7a, as shown in Scheme 1. The two products
were separated by chromatography and their structural determina-
tion was achieved following their analytical and spectroscopic data
and, for 7a, unequivocally established by X-ray crystal analysis,
as shown in Fig. 2 (see ESIw).
In our works focused on the design and synthesis of new
calpain inhibitors, we envisaged the heterocyclic core of
variolins, the pyrido[30,20:4,5]pyrrolo[1,2-c]pyrimidine system
and other related azolopyrimidines as interesting new hetero-
cyclic templates in the development of new calpain inhibitors.5
Two significant structural features of 6a and 7a became
evident. First, the presence of two moieties clearly associated
with the amine used in the reaction, and second the removal of
the bromo substituent from the original C-5 position in 4.
Fig. 1 Structure of alkaloids with a pyrrolo[1,2-a]pyrimidine core.
a
´
Departamento de Quımica Organica, Universidad de Alcala,
28871-Alcala de Henares, Madrid, Spain.
´
´
´
E-mail: juanjose.vaquero@uah.es; Fax: +34-91-8854686;
Tel: +34-91-885476
b Department of Medicinal Chemistry, Centro Nacional de
´
Investigaciones Oncologicas (CNIO), Melchor Fernandez Almagro 3,
E-28029-Madrid, Spain
´
c
´
Departamento de Quımica Inorganica Universidad de Alcala,
28871-Alcala de Henares, Madrid, Spain
´
´
´
w Electronic supplementary information (ESI) available: Experimental
details and characterization of all new compounds. CCDC 884402
(7a). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc34539k
Fig. 2 X-ray crystal structure of 7a.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9171–9173 9171

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Table 1 Reaction of 4a with 2-methoxyethylamine
Table 2 Synthesis of azaindole and indole derivatives 6 and 7
Entry Amine (equiv.) Conditions
6aa (%) 7aa (%)
1
2
3
4
5
6
7
8
9
10
Solvent
Solvent
Solvent
20
20
20
20
20
20
20
100 1C, 1 h
100 1C, 5 h
100 1C, 24 h
Toluene, 100 1C, 2 h
DMF, 100 1C, 2 h
n-PrOH, 100 1C, 2 h
DMF, 100 1C, 7 h
DMF, MW, 100 1C, 10 min 24
DMF, MW, 150 1C, 10 min 52
DMF, MW, 50 1C, 10 min 18
58
43
9
15
50
28
36
36
36
31
3
16
8
15
26
20
24
Yield 6/7a
(%)
Entry Substrate (4)
Amine
1
2
3
MeOCH2CH2NH2
(CH3)2CHNH2
PhCH2NH2
57/34 (6a/7a)
19/49 (6b/7b)
—/42 (6c/7c)
a
By HPLC.
A study of the reaction conditions is shown in Table 1. In all
4
—/67 (6d/7d)
cases 6a and 7a were obtained, with 6a being the major
product under most of the conditions tested. The better yields
were obtained when the amine was used as solvent (Table 1,
entries 1 and 2). Longer reaction times caused extensive decom-
position of both reaction products (entry 3). Other experiments
using an excess of the amine in different solvents afforded lower
yields of 6a and 7a (entries 4–7) and further experiments under
microwave irradiation in DMF (entries 8–10) also gave lower yields
with significant product decomposition (entries 8–10).
5
6
7
8
MeOCH2CH2NH2
CH3(CH2)3NH2
(CH3)2CHNH2
PhCH2NH2
45/41 (6e/7e)
22/52 (6f/7f)
24/17 (6g/7g)
34/42 (6h/7h)
9
33/39 (6i/7i)
10
PhNH2
—/—b
To illustrate the versatility and potential synthetic value of this
reaction for the preparation of these unusual azole derivatives,
we examined the reaction with various representative primary
amines and we tested the reaction with different azolopyrimidine
substrates using the experimental conditions employed in
entry 1 (Table 1). As shown in Table 2, the amine played a
significant role in the composition of the mixture 6a–d/7a–d
(Table 2, entries 1–4). When the substrate was methyl 5-bromo-
pyrido[30,20:4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate (4a), reac-
tion with either 2-methoxyethylamine or isopropylamine produced
mixtures of 6a,b/7a,b, being 6a the major product in the first
case (entry 1), while the latter amine gave 7b as the major
component (entry 2). Even more significant was the behavior
of benzylamine and cyclohexylamine which, respectively,
led to the isolation of 7c and 7d without the corresponding
6c and 6d derivatives being detected in the reaction mixtures
(entries 3 and 4). In the case of methyl 5-bromopyrimido-
[1,6-a]indole-3-carboxylate (4b), all the tested amines afforded
mixtures of 6e–i/7e–i (entries 5–9), except for the case of
aniline, with which no product could be detected after heating
for 24 h (entry 10).
11
MeOCH2CH2NH2
27/70 (6k/7k)
12
MeOCH2CH2NH2
—/41 (6l/7l)
13
MeOCH2CH2NH2
—/—b
Two 4-substituted azaindoles (4c and 4d) were also reacted
with 2-methoxyethylamine with very different results for each
substrate. Thus, 4c, bearing a methoxy group at C-4, produced a
97% yield mixture of both imidazolones 6k/7k (entry 11), whereas
4d, the substrate having a chloro substituent at C-4, produced the
only isolated product 7l in a moderate yield (entry 12). It is
noteworthy that neither a pyrrolopyrimidine (4e) nor a pyrazolo-
pyrimidine (4f) underwent the pyrimidine ring-opening reaction
described for 4a–d, with the corresponding amides being isolated
in 63% and 53% yield, respectively.
a
b
Isolated yields. The corresponding amide was obtained.
with 2-methoxyethylamine as with 4a–f. Our results showed
that the amide 5g was the only formed product along with
some starting material which was not consumed after refluxing
for 24 h (Scheme 2).
In the light of these results, a plausible mechanistic hypothesis
would involve a cascade process starting with the initial formation
of the amide 5, which would further react with a second equivalent
of the amine to cause the ring-opening of the pyrimidine ring
via intermediate I. Formation of 6 and 7 can be rationalized
from the formamidine-type intermediates IIa and IIb throughout
a 5-exo-trig cyclization for 67 and an intermolecular Michael
In order to know the role of the bromo substituent at C-5
in the ring opening reaction of the pyridopyrrolopyrimidine
and pyrimidoindole systems, methyl pyrimido[1,6-a]indole-3-
carboxylate (4g) was prepared and subjected to the same reaction
c
9172 Chem. Commun., 2012, 48, 9171–9173
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In summary, we have shown that bromo substituted
pyrido[30,20:4,5]pyrrolo[1,2-c]pyrimidine and pyrimido[1,6-a]-
indole methyl carboxylates react with a variety of primary
amines leading to novel and unusual substituted indoles or
azaindoles. This was rationalized with a cascade process
consisting of pyrimidine ring-opening and imidazolone ring-
forming reactions, and involving either two or three amine
equivalents. Ongoing studies have shown that some derivatives 7
possess a very high calpain inhibitory activity, but derivatives 6
are inactive. Moreover, compounds 6 are structurally related
to green fluorescent protein chromophores,9 and are highly
fluorescent but the presence of the amine moiety makes
compounds of type 7 less fluorescent.
Scheme 2 Reaction of pyrimidoindoles 4g and 4h with 2-metoxy-
ethylamine.
Financial support from the Spanish Ministerio de Ciencia e
Innovacio
Carlos III (REDinREN, RD6/0016/0016), University of
Alcala (UAH2011/EXP-027) and a grant from the University
of Alcala (M. M.) are gratefully acknowledged. We also thank
´
n (project CTQ2011-24715), Instituto de Salud
´
´
Dr Alberto Domingo for pictures of some fluorescent dyes.
Notes and references
1 J. J. Vaquero and J. Alvarez-Builla, Heterocycles Containing
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Weinheim, 2011, vol. 4, ch. 22, pp 1989–2070.
2 (a) K. Higuchi, Y. Sato, M. Tsuchimochi, K. Sugiura, M. Hatori
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Tetrahedron Lett., 1987, 28, 5561.
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Munro, S. Parkin and H. Hope, Tetrahedron, 1994, 50, 3987;
(b) G. Trimurtulu, D. J. Faulkner, N. B. Perry, L. Ettouati,
M. Litaudon, J. W. Blunt, M. H. G. Munro and G. B. Jameson,
Tetrahedron, 1994, 50, 3993.
4 (a) A. Baeza, J. Mendiola, C. Burgos, J. Alvarez-Builla and
J. J. Vaquero, Eur. J. Org. Chem., 2010, 5607; (b) S. R. Walker,
E. J. Carter, B. C. Huff and J. C. Morris, Chem. Rev., 2009,
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5 (a) I. O. Donkor, Expert Opin. Ther. Pat., 2011, 21, 601;
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Chem., 2010, 10, 270; (c) M. E. Saez, R. Ramirez-Lorca,
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6 (a) J. Mendiola, A. Baeza, J. Alvarez-Builla and J. J. Vaquero,
J. Org. Chem., 2004, 69, 4974; (b) J. Mendiola, J. M. Minguez,
J. Alvarez-Builla and J. J. Vaquero, Org. Lett., 2000, 2, 3253.
7 Although cyclization of intermediates IIb could give compounds 6
as Z–E mixtures, NMR studies (see ESIw) showed that the E isomer
was exclusively formed in every case. For instance, with compound
6e, irradiation at the CH2CH2OMe residue attached to imidazolone’s
N-3 (3.78 ppm) resulted in nOe interaction with indole’s H-3
(7.75 ppm), which was only compatible with the E configuration of
its exocyclic double bond.
Scheme 3 Tentative mechanism for the formation of 6–7.
reaction involving a third amine equivalent followed by an
intramolecular cyclization for 7 (Scheme 3).
Additional support for this mechanism was provided by
attempted reaction of methyl-5-phenylpyrimido[1,6-a]indole-
3-carboxylate (4h) with 2-methoxyethylamine that allowed
the isolation of the corresponding amide derivative 8h,
(Scheme 2), this latter being produced by nucleophilic attack
of the amine at the C-1 position of the pyrimidoindole ring
and loss of hydrogen.8
8 This reaction gave complex reaction mixtures from which the amide,
8h and a small amount of an unidentified product were isolated.
9 (a) S. J. Remington, Protein Sci., 2011, 20, 1509; (b) T. D. Craggs,
Chem. Soc. Rev., 2009, 38, 2865.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9171–9173 9173